Bis(5-aeyl-2-pyridyl) derivatives

ABSTRACT

A bis(5-aryl-2-pyridyl) compound represented by formula (1) or a salt thereof:  
                 
 
wherein A is a substituted or unsubstituted aromatic hydrocarbyl group or a substituted or unsubstituted aromatic heterocyclic group, and X is a group selected from the group consisting of moieties having formulas (2) to (5):  
                 
wherein, in formula (2), m is an integer of 1 or 2; in formula (3), n is an integer of 1 to 6; and in formula (4), R is hydrogen or a lower alkyl group and p is an integer of 1 to 6.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to bis(5-aryl-2-pyridyl) derivatives orsalts thereof, and also to medicinal compositions which comprise thebis(5-aryl-2-pyridyl) derivatives or salts-thereof as active ingredientsand are useful for the prevention or treatment of allergic immunediseases.

2. Discussion Of the Background

IgE, a class of immunoglobulin (Ig), is an allergen-specific moleculeproduced by IgE producing cells differentiated from B cells, whentriggered by contact of immunocytes with an allergen in the body.

IgE is produced in an organ targeted by allergy, and binds to a receptoron-surfaces of mast cells which are the principal effector cells in anallergic reaction or basophils (sensitized state). From the mast cells,which are stimulated as a result of intrusion of the allergen into thebody after sensitization and the accompanying reaction with the specificIgE, allergic chemical mediators such as histamine, leucotrienes,prostaglandins and PAF, and tissue destructive enzymes such as tryptaseare released thereby provoking the immediate responses of an allergicreaction such as increased vasopermeability, smooth muscle constrictionor vasodilation. From the stimulated mast cells, cytokines, such asIL-4, which directly activate other immune system cells are alsosecreted. As a result, eosinophils, basophils or the like infiltratetissues, and allergic chemical mediators or tissue destructive proteinssuch as MBP, which are secreted by these inflammatory cells, induceslate responses of an allergic reaction to protract and worsen anallergic symptom.

As can be appreciated from the foregoing remarks, an abnormality in IgEproduction is highly relevant to various allergic immune diseases suchas asthma, atopic dermatitis, allergic rhinitis, inflammatory boweldisease, contact dermatitis and allergic ophthalmopathy. It is knownthat inhibition of IgE production makes it possible to prevent and/ortreat these diseases (Emerging Therapeutic Targets In Asthma AndAllergy: Modulation Of IgE, Emerging Therapeutic Targets, 3, 229-240(1990); Anti-IgE As Novel Therapy For The Treatment Of Asthma, Curr.Opin. Plum. Med., 5, 76-80 (1999); Treatment Of Allergic, Asthma WithMonoclonal Anti-IgE Antibody, N. Eng. J. Med., 341, 1966-1973 (1999);Anti-IgE Antibody Therapy For Asthma, N. Eng. J. Med., 341, 2006-2008(1999)).

From the foregoing, IgE is believed to be a substance which takes partin the manifestation of an allergic disease at the onset of the disease.With the objective of developing antiallergic agents, some smallmolecules with IgE antibody production inhibiting activity have beenfound and reported to date (WO 98/04058, WO 98/07702, WO 98/16497, JP10-324631AA, WO 99/19291, WO 99/35140, WO 99/38829, WO-99/42446, JP11-269192A, WO 00/05198, “Yakuri to Chiryo (Basic Pharmacology &Therapeutic)” 22(3), 1369 (1994), JP 1-106818A, JP 7-17506B, JP 8-92216A, JP 8-109177A, WO 96/11682, JP 59-167564A). These compounds, however,involve problems such as low solubility in water, and therefore they arenot entirely satisfactory agents in the therapeutic treatment ofallergic disease.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide acompound having excellent IgE antibody production inhibiting activityand also a medicinal composition comprising the compound as an activeingredient.

Briefly, this object and other objects of the present invention ashereinafter will become more readily apparent can be attained by abis(5-aryl-2-pyridyl) compound having the following formula (1) or asalt thereof:

wherein A is a substituted or unsubstituted aromatic hydrocarbon groupor a substituted or unsubstituted aromatic heterocyclic group, and X isa substituent selected from the group consisting of formulas (2) to (5):

wherein, in formula (2), m is an integer of 1 or 2; in formula (3), n isan integer of 1 to 6; and in formula (4), R is hydrogen or lower alkyland p is an integer of 1 to 6.

Another aspect of the present invention is a medicinal compositioncomprising the active bis(5-aryl-2-pyridyl) compound or the salt thereofof the invention.

Still another aspect of the present invention is a medicinal compositioncomprising the active bis(5-aryl-2-pyridyl) compound or the salt thereofin combination with a pharmacologically acceptable carrier.

Yet another aspect of the present invention is a method of treating asubject for an allergic immune disease by administering thebis(5-aryl-2-pyridyl) derivative or the salt thereof of the invention toa subject.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As a result of the investigative work by the present inventors, thepresent compound, has been found to exhibit an excellent IgE antibodyproduction inhibiting activity and also good solubility in later, andtherefore are useful in the treatment of allergic immune diseases.

Illustrative of the lower alkyl moiety in “lower alkyl groups”,“halogeno(lower alkyl) groups”, “hydroxy(lower alkyl) groups”, “loweralkoxy(lower alkyl) groups”, “lower alkoxy groups”, “(lower alkylthiogroups”, “(lower alkyl)amino groups”, “(lower alkyl)sufonylaminogroups”, “(lower alkoxy)carbonyl groups” and “lower alkanoyl groups” asused herein are linear, branched or cyclic alkyl groups having 1 to 6carbon atoms. Suitable examples of lower alkyl groups include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl, cyclopropyl, and cyclohexyl. Further, suitable halogenatoms include fluorine, chlorine, bromine and iodine.

In formula (1), the aromatic hydrocarbon group represented by Apreferably has 6 to 14 carbon atoms, with phenyl or naphthyl being morepreferred and phenyl being particularly preferred. Preferred examples ofthe aromatic heterocyclic group include 5- to 10-membered heterocyclicgroups each of which contains one or two nitrogen, oxygen or sulfuratoms, with pyridyl, thienyl, furyl, benzofuryl and benzothienyl groupsbeing more preferred. These groups may contain 1 to 3 substituents.Suitable examples of such substituents include lower alkyl groups,halogeno(lower alkyl) groups, hydroxy(lower alkyl) groups, loweralkoxy(lower alkyl) groups, lower alkoxy groups, halogen atoms, hydroxygroup, cyano group, (lower alkyl)thio groups, amino group, mono- ordi-(lower alkyl)amino groups, (lower alkyl)sufonylamino groups, formylgroup, carboxyl group, (lower alkoxy)carbonyl groups, lower alkanoylgroups, pyrrolidinyl group and alkylenedioxy groups.

Preferred specific examples of these substituents include methyl,t-butyl, trifluoromethyl, hydroxymethyl, methoxymethyl, methoxy, ethoxy,isopropoxy, fluoro, chloro, hydroxy, cyano, methylthio, amino,dimethylamino, methanesulfonylamino, pyrrolidinyl, formyl, carboxyl,methoxycarbonyl, ethoxycarbonyl, acetyl, and methylenedioxy.

Among the groups represented by X, preferred is the group of formula (3)in which n is an integer of 2 to 4 and the group of formula (4) in whichp is an integer of 2 to 4.

Preferred specific examples of the bis(5-aryl-2-pyridyl) derivative (1)of the present invention include1,4-bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinedimethanesulfonate,1,4-bis[5-(4-amino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinetetrahydrochloride,1,4-bis[5-(4-dimethylamino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine,1,3-bis[4-[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]-1-piperazinyl]propane,andN,N′-bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]-N,N′-dimethylethylenediaminedimethanesulfonate.

Compound (1) of the present invention can be produced, for example, bythe following sequence of reaction steps, although no particularlimitation is imposed on the method of synthesis employed.

wherein A and X have the same meanings as defined above, Y¹ and Y² eachare halogen or —OSO₂(C_(q)F_(2q+1)) in which q is 0 or an integer of 1to 4, and Z is dihydroxyboron, di(lower alkoxy)boron, di(loweralkyl)boron, dihalo(lower alkyl)silicon, halogenated zinc, tri(loweralkyl)tin, halogenated magnesium or the like.

Specifically, compound (1) of the present invention can be produced byreacting compound (6) with compound (7) in the absence of a solvent orin a solvent optionally in the presence of a base to prepare compound(8) and then reacting compound (8) with compound (9).

Suitable examples of the solvent employed in the reaction (condensationreaction) between compound (6) and compound (7) include toluene,tetrahydrofuran, dioxane and dimethylformamide, whereas examples of thebase employable in the reaction include potassium carbonate and sodiumhydride. The reaction is preferably conducted at room temperature to200° C. for 0.5 to 100 hours, notably at 80 to 120° C. for 2 to 15hours.

To prepare compound (1) of the present invention, the reaction(cross-coupling reaction) between compound (8) and compound (9) can beconducted by adding compound (9) and a catalyst to a solution orsuspension of compound (8) and allowing compound (8) to react withcompound (9) optionally in the presence of a ligand and a base(Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J.,Eds.; Wiley-VHC: Weinheim (1998). Stanforth, S. P., Tetrahedron, 54,263-303 (1998)).

Suitable examples of a solvent employable in the above reaction includebenzene, toluene, xylene, diethyl ether, tetrahydrofuran,dimtethoxyethane, dioxane, acetonitrile, dimethylformamide,N-methylpiperidone, methanol, ethanol, and water. Suitable examples ofthe catalyst include tetrakis(triphenylphosphine)palladium(0),tris(bisbenzylideneacetone)dipalladium(0), palladium(II) acetate,palladium(II) chloride dichlorobis(triphenylphosphine)pal ladium(II),dichloro[1,2-bis(diphenylphosphino)ethane]palladium(II),dichloro[1,4-bis(diphenylphosphino)butane]palladium(II),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II),tetrakis(triphenylphosphine)nickel(0) andbis(acetylacetonato)nickel(II).

Suitable examples of the ligand, on the other hand, includetri(t-butyl)phosphine, triphenylphosphine, tri(o-tolyl)phosphine,tri(2-furyl)phosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane,1,4-bis(diphenylphosphino)butane, and1,1′-bis(diphenylphosphino)ferrocene. Suitable examples of the baseinclude-sodium acetate, potassium carbonate, sodium carbonate, sodiumhydrogencarbonate; potassium phosphate, sodium hydroxide, potassiumhydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, cesiumfluoride, tributylammonium fluoride, and triethylamine.

As to the reaction conditions, the reaction may be conducted at roomtemperature up to a temperature of 150° C. for 0.5 to 100 hours. It is,however, preferred to follow the details of the reaction reported bySuzuki et al, (Miyaura, N.; Suzuki, A., Chem. Rev., 95, 2457-2483 (199Here, compound (9) is employed in which Z is dihydroxyboron and thereaction is conducted under conditions oftetrakis(triphenylphosphine)palladium(0)/potassium carbonate (or sodiumcarbonate)/water-methanol(or ethanol)-toluene/60 to 100° C./0.5 to 3hours; or a compound (9) in which Z is di(lower alkoxy)boron is reactedunder conditions ofdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)/1,1′-bis(diphenylphosphino)ferrocene/sodiumcarbonate/water-dimethylformamide/60 to 100° C./0.5 to 3 hours.

The compounds obtained in the above reactions, respectively, can beisolated and purified by subjecting them to purification procedurescommonly employed in synthetic organic chemistry, for example,filtration, extraction, washing, drying, concentration,recrystallization, one or more of various types of chromatography, andthe like. Further, the intermediate can be provided for use in the nextreaction without the need of specifically purifying the compound.

In addition, the product and intermediate may also be obtained in theform of solvates with reaction solvents, recrystallization solvents orthe like, especially as hydrates. Further, compound (1) of the presentinvention may include various isomers depending on the kinds andcombination of substituents in the molecule. It is to be noted that thepresent invention encompasses all of such isomers.

Compound (1), obtained as described above, can be converted into an acidaddition salt or a basic salt by a method known per se in the art. Noparticular limitation is imposed on such salts insofar as they arepharmacologically acceptable salts. When compound (1) is a basiccompound, examples of a pharmacologically acceptable salt thereofinclude mineral acid salts such, as the hydrochloride, sulfate andnitrate; and organic acid salts such as the methanesulfonate, acetate,oxalate and citrate. When compound (1) is an acidic compound, on theother hand, examples of pharmacologically acceptable salts thereofinclude alkali metal salts such as the sodium and potassium salts;alkaline earth metal salts such as the calcium and magnesium salts, andorganic base salts such as the pyridine, picoline and triethylaminesalts.

The bis (5-aryl-2-pyridyl) compound (1) of the present invention hasexcellent IgE antibody production inhibiting activity as is demonstratedin tests described below, as well as IL-4 production inhibiting activityand IL-5 production inhibiting activity. The compound is useful asmedicinal agent for the prevention or treatment of various allergicdiseases, for example, asthma, atopic dermatitis, allergic rhinitis,inflammatory bowel disease, contact dermatitis and allergicophthalmopathy, and also as an IgE antibody production inhibitor.

The medicinal composition of the present invention comprises, as anactive ingredient, the bis(5-aryl-2-pyridyl) compound or a salt thereof.By adding pharmacologically acceptable, inorganic or organic carriers,the bis(5-aryl-2-pyridyl) compound or salt thereof can be formulatedinto medicinal compositions, for example, various oral preparations orparenteral preparations such as solid, semi-solid or liquid preparationsby methods known per se in the art.

Illustrative of preparations for oral administration are tablets, pills,granules, soft br hard capsules, triturates, subtilized granules,powders, emulsions, syrups, pellets, and elixirs. On the other hand,illustrative preparations for parenteral administration includeinjectable formulations, drips, infusions, ointments, lotions, tonics,sprays, suspensions, medicinal oils, emulsions, suppositories, andinstillation.

To formulate such preparations, methods known per se in the art can befollowed. The active ingredient of the present invention can be used incombination with pharmacologically acceptable surfactants, excipients,coloring agents, flavoring agents, preservatives, stabilizers, bufferingagents, suspending agents, isotonicities and the like as needed.

The dosage of the therapeutic agent of the present invention variesinter alia depending on the compound, the disease to be treated orprevented, the method of administration, the period of treatment, and,the age, sex and weight of the patient. Nonetheless, it is preferred toadminister the medicine at a daily dosage ranging from 0.01 to 1,000mg/kg-weight in terms of the compound represented by formula (1). Thisdosage can be administered at once or in several portions, for example,2 to 6 portions in a day.

Having now generally described this invention, a further understandingcan be obtained by reference to certain specific examples which areprovided herein for purposes of illustration only and are not intendedto be limiting unless otherwise specified.

REFERENCE EXAMPLE 1 1,4-Bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine

To a solution of hexahydro-1,4-diazepine (2.84 g, 28.4 mmol) indimethylformamide (14 mL) were added 2,5-dibromopyridine (16.23 g, 68.5mmol) and potassium carbonate powdered in a mortar (8.00 g, 57.9 mmol),and the resultant mixture was stirred at 1200 for 15 hours. Water wasadded to the reaction mixture, and the mixture was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel to yield crude crystals of the titlecompound (7.67 g, yield: 66%). The crude crystals were recrystallizedfrom chloroform-hexane to give colorless fine needles (melting point:178.0-181.0° C.

REFERENCE EXAMPLE 2 3,5-Dimethoxyphenylboronic Acid

Under argon, to anhydrous tetrahydrofuran (9.0 mL) stirred in a dryice-methanol bath was gradually added a 1.57 M solution ofn-butyllithium in hexane (3.9 mL, 5.9 mmol), followed by the dropwiseaddition of a solution of 3,5-dimethoxyiodobenzene (713.0 mg, 2.70 mmol)in anhydrous tetrahydrofuran (5.0 mL). After the mixture was stirred for20 minutes in the dry ice-methanol bath, triisopropyl borate (0.75 mL,3.2 mmol) was added and the mixture was additionally stirred for 20minutes. The reaction mixture was stirred at room temperature for 1 hourand concentrated under reduced pressure, then a 1.0 M aqueous sodiumhydroxide (7.0 mL) was added to the residue. The resulting aqueoussolution was washed with chloroform, acidified by adding concentratedhydrochloric acid, and extracted with chloroform. The organic layer waswashed with brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The residue was recrystallized fromchloroform-hexane to yield the title compound as a colorless crystallinepowder (melting point: 159.0-161.0° C.)(367.0 mg, yield: 91%).

REFERENCE EXAMPLE 3 3,5-Diisopropoxyphenyl trifluoromethanesulfonate

To a solution of 3,5-diisopropoxyphenol (J. Chem. Soc. Perkin Trans., 1,17, 2939-2942 (1998)). (170.0 mg, 0.810 mmol) in methylene chloride (4.5mL) was added N,N-diisopropylethylamine (195.0 mg, 1.50 mmol). Theresulting solution was cooled in a dry ice-methanol bath, andtrifluoromethanesulfonic anhydride (367.0 mg, 1.30 mmol) was addeddropwise over approximately 10 minutes., After stirring for 3 hours,brine was added to the reaction mixture, and the mixture was extractedwith chloroform. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel to yield the titlecompound as a pale yellow oil (261.0 mg, yield: 94%).

REFERENCE EXAMPLE 4 3,5-Bis(methoxymethyl)phenyltrifluoromethanesulfonate

To an ice-cold stirred solution of dimethyl 5-hydroxyisophthalate (J.Org. Chem., 65, 5360-5370 (2000)). (1.25 g, 5.95 mmol) in anhydrousdimethylformamide (10 mL) were added imidazole (0.83 g, 12.2 mmol) andt-butylchlorodiphenylsilane (2.2 mL, 8.5 mmol). After stirring in icefor 15 minutes and at room temperature for 2 hours, water was added andthe mixture was extracted with benzene-hexane (1:1). The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford an oil (3.40 g) containing dimethyl5-(t-butyldiphenylsiloxy)isophthalate.

Lithium aluminum hydride (1.00 g, 26.4 mmol) was added to an ice-coldsolution of the oil (3.22 g) obtained by the above-described procedure,in anhydrous tetrahydrofuran (35 mL), and the mixture was stirred for 20minutes. Methanol (7.0 mL, 170 mmol) was added to the reaction mixture,and the ice bath was removed. Water (7.0 mL), diethyl ether (150 mL),and anhydrous magnesium sulfate (30 g) were added, and the mixture wasstirred at room temperature for 3 hours, then insoluble materials wereremoved by filtration through Celite. The residue was flashed withchloroform, then the filtrate and the washing were combined andconcentrated under reduced pressure. The residue was recrystallized fromdiethyl ether-hexane to yield1-t-butylphenylsiloxy-3,5-bis(hydroxymethyl)benzene as colorless needles(melting point: 132.0-133.0° C.) (1.76 g, yield: 75% based on dimethyl5-hyroxyisophthalate).

Methyl iodide (0.80 mL, 13 mmol) and a 50% dispersion of sodium hydridein mineral oil (156.5 mg, 3.26 mmol) were added to an ice-cold solutionof 1-t-butyldiphyenylsiloxy-3,5-bis(hydroxymethyl)benzene (501.3 mg,1.28 mmol) in dimethylformamide (5.0 mL), and the mixture was stirredfor 1 hour. Water was added to the reaction mixture, and the mixture wasextracted with benzene-hexane (1:1). The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford an oil (0.60 g) containing1-t-butyldiphenylsiloxy-3,5-di(methoxymethyl)benzene.

A 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (2.0mL, 2.0 mmol) was added to an ice-cold solution of the oil (0.60 g)obtained by the above-described procedure in tetrahydrofuran (8.0 mL),and the mixture was stirred for 15 minutes. An approx. 20% aqueousammonium chloride was added, and the mixture was extracted with diethylether. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel to yield 3,5-bis(methoxymethyl)phenol as acolorless oil [219.8 mg, yield: 94% based on1-t-butyldiphenylsiloxy-3,5-bis(hydroxymethyl)benzene].

By a similar procedure as in Reference Example 3, the title compound wasobtained as a colorless oil (343.9 mg, yield: 93%) from3,5-bis(methoxymethyl)phenol (215.4 mg, 1.18 mmol).

REFERENCE EXAMPLE. 5 3,4,5-Triethoxyphenylboronic Acid

A solution of 3,4,5-triethoxybenzoic acid (20.0 g, 78.7 mmol) in aceticacid (68 mL) was stirred at 15° C., and concentrated nitric acid (d1.38)(34 mL, 750-mmol) was added. After stirring at room temperature for1 hour, the reaction mixture was poured into ice water and the mixturewas extracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium hydrogencarbonate and brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to yield3,4,5-triethoxy-1-nitrobenzene as a colorless oil (12.9 g, yield: 64%).

To a solution of 3,4,5-triethoxy-1-nitrobenzene (12.9 g, 50.5 mmol) inmethanol (445 mL) were added 10% palladium on charcoal (6.7 g) andammonium formate (16.2 g, 253 mmol), and the mixture was stirred at 70°C. for 1 hour. Insoluble materials were removed by filtration throughCelite, and the filtrate was concentrated under reduced pressure. Asolution of the residue in chloroform was washed with water and brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to afford an oil (10.5 g) containing 3,4,5-triethoxyaniline.

The oil (9.5 g, approx. 42.2 mmol) obtained by the above procedure wassuspended in water (200 mL). Concentrated sulfuric acid (7.3 mL, 88mmol) was added to the ice-cold suspension to provide a homogeneoussolution. A solution of sodium nitrite (3.10 g, 44.0 mmol) in water (10mL) was added dropwise to the ice-cold solution over approximately 10minutes, and the solution was stirred for 15 minutes, followed by theaddition of a solution of potassium iodide (7.70 g, 46.0 mmol) in water(10 mL). The reaction mixture was stirred at room temperature for 1 hourand at 50° C. for 15 minutes, and extracted with ethyl acetate. Theorganic layer was bashed with brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by column chromatography silica gel to yield3,4,5-triethoxy-1-iodobenzene as pale yellow needles (melting point:44.0-46.0° C.)(11.60 g, yield: 75%).

By a similar procedure as in Reference Example 2, crude crystals wereobtained from 3,4,5-triethoxy-1-iodobenzene (5.00 g, 14.9 mmol). Thecrude crystals were recrystallized from chloroform-hexane to yield thetitle compound as colorless needles (melting point. 167.0-168.0° C.)(1.80 g, yield: 48%).

REFERENCE EXAMPLE 6 3,5-Diisopropoxy-4-methoxyphenylboronic Acid

To a solution of methyl 3,5-dihydroxy-4-methoxybenzoate (Ann. Chem.,544, 62-71 (1940)). (4.40 g, 22.2 mmol) in dimethylformamide (44.0 mL)were added potassium carbonate (10.20 g, 73.8 mmol) and isopropyl iodide(19.66 g, 115 mmol). After stirring at 70° C. for 3 hours, water wasadded to the reaction mixture. The resulting mixture was extracted withdiethyl ether. The organic layer vas dried over anhydrous sodium sulfateand then concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel to yield methyl3,5-diisopropoxy-4-methoxybenzoate as a pale yellow oil (4.16 g, yield:66%).

To a solution of methyl 3,5-diisopropoxy-4-methoxybenzoate (4.16 g, 14.7mmol) in methanol(20 mL) a 5.0 M aqueous sodium hydroxide (20.0 mL, 100mmol) was added. After stirring at 80° C. for 3 hours, the reactionmixture was concentrated under reduced pressure to remove the methanol.The residue was acidified by the addition of concentrated hydrochloricacid and extracted with chloroform. The organic layer was washed withbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure to yield an oil (4.00 g) containing3,5-diisopropoxy-4-methoxybenzoic acid.

The following synthetic procedure was carried out according to theprocedure of Reference Example 5. From the oil (3.70 g) obtained by theabove-described procedure, 3,5-diisopropoxy-4-methoxy-1-nitrobenzene(1.70 g) was obtained as a pale yellow oil (yield: 46% based on methyl3,5-diisopropoxy-4-methoxybenzoate). From3,5-diisopropoxy-4-methoxy-1-nitrobenzene (1.70 g, 6.30 mmol),1-iodo-3,5-diisopropoxy-4-methoxybenzene was obtained as a pale yellowoil (1.45 g, yield: 66%). From 1-iodo-3,5-diisopropoxy-4-methoxybenzene.(700.0 mg, 2.17 mmol), the title compound was obtained as a colorlesscrystalline powder (melting point: 159.0-161.0° C.) (367.0 mg, yield:70%).

REFERENCE EXAMPLE 7 3-Methoxy-4,5-methylenedioxyphenylboronic Acid

To a solution of 3-hydroxy-4,5-methylenedioxybenzoic acid (Liebigs Ann.Chem., 361-364 (1994)) (3.90 g, 20.0 mmol in dimethylformamide (20.0 mL)were added potassium carbonate (2.80 g, 20.0 mmol) and methyl iodide(4.30 g, 30.0 mmol), and the mixture was stirred at 50° C. for 1 hour.Water was added to the reaction mixture, and the mixture was extractedwith diethyl ether. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel to yield methyl3-methoxy-4,5-methylenedioxybenzoate as a colorless viscous oil (4.30 g,yield: 98%).

Synthesis of the title compound from methyl3-methoxy-4,5-methylenedioxybenzoate was carried out by applying thesynthetic procedure of 3,5-diisdpropoxy-4-methoxyphenylboronic acid frommethyl 3,5-diisopropoxy-4′ methoxybenzoate in Reference Example 6. Frommethyl 3-methoxy-4,5-methylenedioxybenzoate (4.30 g, 20.5 mmol),3-methoxy-4,5-methylenedioxybenzoic acid (3.00 g) was obtained ascolorless prisms (melting point: 215.0-216.0° C.) (yield: 71%). From3-methoxy-4,5-methylenedioxybenzoic acid (2.50 g, 12.7 mmol),3-methoxy-4,5-methylenedioxy-1-nitrobenzene was obtained as a paleyellow amorphous powder (1.26 g, yield: 50%). From3-methoxy-4,5-methylenedioxy-1-nitrobenzene (1.26 g, 16.4 mmol),1-iodo-3-methoxy-4,5-methylenedioxybenzene was obtained as pale yellowneedles (melting point: 71.0-72.0° C.) (1.08 g, yield: 61%). From1-iodo-3-methoxy-4,5 methylenedioxybenzene (750.0 mg, 2.70 mmol), thetitle compound was obtained as a colorless crystalline powder (meltingpoint: 279.0-281.0° C.) (347.0 mg, yield: 66%).

REFERENCE EXAMPLE 8 4-Benzyloxy-3,5-dimethoxyphenylboronic Acid

To a solution of methyl syringate (6.00 g, 28.3 mmol) indimethylformamide (61.0 mL) were added potassium carbonate (2.80 g, 20.3mmol) and benzyl bromide (5.80 g, 33.9 mmol), and the resulting mixturewas stirred at 5° C. for 2 hours. After cooling, water was added, andthe mixture was extracted with diethyl ether. The organic layer waswashed with brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to yield an oil (7.90 g) containing methyl4-benzyloxy-3,5-dimethoxybenzoate.

To a solution of the oil (7.90 g) obtained by the above-describedprocedure in methanol (40 mL) was added a 5.0 M aqueous sodium hydroxide(40 mL, 200 mmol). After stirring at 80° C. for 30 minutes, the reactionmixture was concentrated under reduced pressure to remove the methanol.The residue was acidified by the addition of concentrated hydrochloricacid, and extracted with chloroform. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to afford an oil (6.40 g) containing4-benzyloxy-3,5-dimethoxybenzoic acid.

To a solution of the oil (6.40 g) obtained by the above-describedprocedure in t-butyl alcohol (96 mL) were added triethylamine (2.43 g,23.6 mmol) and diphenylphosphoryl azide (6.40 g, 23.6 mmol). Afterstirring at 100° C. for 2 hours, the reaction mixture was concentratedunder reduced pressure. A solution of the residue in ethyl acetate waswashed with a saturated aqueous sodium hydrogencarbonate and brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel to yield 4-benzyloxy-N-t-butoxycarbonyl-3,5-dimethoxyaniline as acolorless oil (4.56 g, yield: 44% based on methyl syringate).

To a solution of 4-benzyloxy-N-t-butoxycarbonyl-3,5-dimethoxyaniline(590.0 mg, 1.64 mmol) in methanol (2.0 mL) was added a 4.0 M solution ofhydrogen chloride in ethyl acetate (2.0 mL, 8.0 mmol), and the mixturewas stirred at 50° C. for 1 hour. The reaction mixture was concentratedunder reduced pressure, and an 8.0 M aqueous sodium hydroxide (1.5 mL,12 mmol) was added to the residue, then the mixture was extracted withchloroform. The organic layer was washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure toyield an oil (426.0 mg) containing 4-benzyloxy-3,5-dimethoxyaniline.

Synthesis of the title compound from the oil obtained by theabove-described procedure was carried out by applying the syntheticprocedure of 3,4,5-triethoxyphenylboronic acid from the oil containing3,4,5-triethoxyaniline in Reference Example 5. From the oil (426.0 mg,approximately 1.64 mmol) obtained by the above-described procedure,4-benzyloxy-1-iodo-3,5-dimethoxybenzene was obtained as a colorless oil(447.0 mg, yield: 73% based on4-benzyloxy-N-t-butoxycarbonyl-3,5-dimethoxyaniline). From4-benzyloxy-0.1-iodo-3,5-dimethoxybenzene (447.0 mg, 1.21 mmol), thetitle compound was obtained as a colorless crystalline powder (meltingpoint: 180.0-183.0° C.) (87.0 mg, yield: 25%).

REFERENCE EXAMPLE 9 3,5-Dimethoxy-4-methylthiophenylboronic Acid

To a solution of 4-bromo-3,5-dimethoxybenzoic acid (Acta Chem. Scand.,2, 34-41, (1948)) (22.6 g, 86.6 mmol) in methylene chloride (400 mL) wasadded dimethylformamide (1.5 mL, 19.4 mmol). Oxalyl chloride (13.0 g,102.0 mmol) was gradually added to the ice-cold solution, and themixture was stirred at room temperature for 1 hour and 30 minutes. Thereaction mixture was concentrated under reduced pressure to yield crudecrystals of 4-bromo-3,5-dimethoxybenzoyl chloride. To an ice-coldsolution of 2-amino-2-methylpropanol (8.40 g, 94.2° mmol) in methylenechloride (100 mL) were added N,N-diisopropylethylamine (16.6 mL, 95.3mmol) and a solution of the crude 4-bromo-3,5-dimethoxybenzoyl chloridein methylene chloride (200 mL). After the mixture was stirred at roomtemperature for 10 minutes, the mixture was washed successively withwater, 8.0 M hydrochloric acid, a saturated aqueous sodiumhydrogencarbonate and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. Thionyl chloride (47.5 mL, 651.0mmol) was added to the residue, and the mixture was stirred at roomtemperature for 10 minutes. To the reaction mixture were added ice waterand a 2.5 M aqueous sodium hydroxide (600 mL, 1500 mmol), and themixture was extracted with diethyl ether. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was recrystallized form diethylether-hexane to yield2-(4-bromo-3,5-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline as colorlessfine needles (melting point: 172.5-174.5° C.) (20.9 g, yield: 77%).

Under argon, to a solution of2-(4-bromo-3,5-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline (51.43 g, 0.164mmol) in anhydrous tetrahydrofuran (1000 mL) stirred in a dryice-methanol bath were added dropwiseN,N,N′,N′-tetramethylethylenediamine (30.0 mL, 0.199 mol) and a 1.59 Msolution of n-butyl lithium in hexane (134.0 mL, 0.213 mol). Afterstirring for 10 minutes, dimethyl disulfide (198.0 mL, 0.200 mmol) wasadded. After stirring further for 1 hour, water was added to thereaction mixture, the organic solvents were removed by concentrationunder reduced-pressure, and the residue was extracted with diethylether. The organic layer was washed with brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue wasrecrystallized from diethyl ether-hexane to yield.2-(4-methylthio-3,5-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline ascolorless fine needles (melting point: 82.5-84.5° C.) (34.80 g, yield:0.76%).

A solution of2-(4-methylthio-3,5-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline (34.70 g,0.123 mmol) in 3.0 M hydrochloric acid (450 mL) was stirred at 100° C.for 3 hours, and the reaction mixture was extracted withmethanol-chloroform (1:10). The organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. To a solution of the residue in methanol (50 mL) was added a2.5 M aqueous sodium hydroxide (100 mL, 0.25 mol), and the resultingmixture u as stirred at 100° C. for 1 hour. The ice-cold reactionmixture was acidified by the addition of concentrated hydrochloric acid,and extracted with methanol-chloroform (1:10). The organic layer waswashed with brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to yield an oil (30.72 g) containing3,5-dimethoxy-4-methylthiobenzoic acid.

Synthesis of the title compound from the oil obtained by theabove-described procedure was carried out by applying the syntheticprocedure of 4-benzyloxy-3,5-di methoxyphenylboronic acid from the oilcontaining 4-benzyloxy-3,5-dimethoxybenzoic acid in Reference Example 8.From the oil (30.72 g) obtained by the above-described procedure,N-t-butoxycarbonyl-3,5-dimethoxy-4-methylthioaniline was obtained ascolorless fine crystals (melting point: 123.5-125.5° C.) [26.33 g,yield: 71% based on2-(4-methyl-thio-3,5-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline]. FromN-t-butoxycarbonyl-3,5-dimethoxy-4-methylthioaniline (12.74 g, 42.6mmol), 1-iodo-3,5-dimethoxy-4-methylthiobenzene was obtained as a browncrystalline powder (melting point: 103.0-104.0° C.) (8.90 g, yield:67%). From 1-iodo-3,5-dimethoxy-4-methylthiobenzene (6.90 g, 22.2 mmol),the title compound was obtained as a colorless crystalline powder(melting point: 262.0-265.0° C.) (4.11 g, yield: 82%).

REFERENCE EXAMPLE 10 4-Chloro-3,5-dimethoxyphenylboronic Acid

A solution of sodium nitrite (97.0 mg, 1.40 mmol) in water (2.0 mL) wasadded dropwise to an ice-cold suspension of 4-bromo-2,6-dimethoxyaniline(Z. Naturforsch., B24(5), 524-527 (1969)) (232.0 mg, 1.00 mmol) in 6.0M-hydrochloric acid (2.5 mL). After stirring in ice for 30 minutes, asolution of cupric chloride (495.0 mg, 5.00 mmol) in concentratedhydrochloric acid (2.0 mL) was added. The reaction mixture was stirredat room temperature for 30 minutes and at 100° C. for 2 hours, andextracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium hydrogencarbonate and water, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to yield1-bromo-4-chloro-3,5-dimethoxybenzene as a colorless amorphous powder(230.0 mg, yield: 92%).

By a similar procedure to that described in Reference Example 2, crudecrystals were obtained from 1-bromo-4-chloro-3,5-dimethoxybenzene (160.0mg, 0.630 mmol). The crude crystals were purified by columnchromatography on silica gel to yield the title compound as a colorlessamorphous powder (90.0 mg, yield: 66%).

REFERENCE EXAMPLE 11 4-Cyano-3,5-dimethoxyphenylboronic Acid

Following the procedure of the synthesis of3,4,5-triethoxy-1-iodobenzene from the oil containing3,4,5-triethoxyaniline in Reference Example5,1-iodo-3,5-dimethoxy-4-methylbenzene was obtained as a pale yellowamorphous powder (7.59 g, yield: 870%) from3,5-dimethoxy-4-methylaniline (J. Chem. Soc., 497-506 (1963)) (5.23 g,31.3 mmol).

To a solution of 1-iodo-3,5-dimethoxy-4-methylbenzene (8.05 g, 28.9mmol) in pyridine (83 mL) was added potassium permanganate (27.4 g,173.4 mmol), and the resulting mixture was stirred at room temperaturefor 30 minutes and at 50° C. for 2 hours. Insoluble materials wereremoved by filtration through Celite, and the residue was washed with a0.1 M aqueous sodium hydroxide. The filtrate and the washing werecombined and washed with diethyl ether. The aqueous layer was acidifiedby the addition of concentrated hydrochloric acid, and extracted withchloroform. The organic layer was washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was suspended in hexane and filtered to yield4-iodo-2,6-dimethoxybenzoic acid (5.57 g) as a pale brown crystallinepowder (melting point: 197.5-204.0° C.) (5.57 g, yield: 63%).

Dimethylformamide (15 mg, 0.21 mmol) and oxalyl chloride (0.90 mL, 9.8mmol) were added to an ice-cold solution of 4-iodo-2,6-dimethoxybenzoicacid (2.00 g, 6.50 mmol) in methylene chloride (10 mL). The mixture wasstirred for 20 minutes, followed by the addition of concentrated aqueousammonia (20 mL; 450 mmol). The reaction mixture was stirred at roomtemperature for 20 minutes and concentrated under reduced pressure toyield an oil (2.00 g) containing4-carbamoyl-1-iodo-3,5-dimethoxybenzene.

To a solution of the oil (2.00 g) obtained by the above-describedprocedure in tetrahydrofuran (20 mL) were added carbon tetrachloride(10.0 mL, 104 mmol) and triphenylphosphine (3.50 g, 13.00 mmol), Thereaction mixture was stirred at 50° C. for 20 hours, and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel to yield4-cyano-1-iodo-3,5-dimethoxybenzene as a colorless oil (1.55 g, yield:82% based on 4-iodo-2,6-dimethoxybenzoic acid).

Following the procedure of Reference Example 2, the title compound wasobtained as a colorless amorphous powder (360.0 mg, yield: 72%) from4-cyano-1-iodo-3,5-dimethoxy-benzene (700.0 mg, 2.42 mmol).

REFERENCE EXAMPLE 12 4-(t-Butyldimethylsiloxy)methyl-3,5-dimethoxyphenyltrifluoroimethanesulfonate

To a solution of 3,5-dimethoxyphenol (6.73 g, 43.7 mmol) in anhydrousdimethylformamide (50 mL) were added imidazole (5.95 g, 87.4 mmol) andt-butylchlorodiphenylsilane (15.0 g, 54.6 mmol), and the mixture wasstirred at 50° C. for 4 hours. Water was added to the reaction mixture,and the mixture was extracted with ethyl acetate-hexane (1:2). Theorganic layer was washed with water, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel to yield1-t-butyldiphenylsiloxy-3,5-dimethoxybenzene as a colorless crystallinepowder (melting point: 95.5-96.5° C.) (16.14 g, yield: 94%).

Under nitrogen, a 1.60 M solution of n-butyl lithium in hexane (31 mL,49 mmol) was added to a solution of1-t-butyldiphenylsiloxy-3,5-dimethoxybenzene (14.68 g, 39.0 mmol) inanhydrous diethyl ether (200 mL) stirred in an ice bath. The reactionmixture was stirred at 35° C. for 3 hours and cooled in the ice bath,followed by the addition of dimethylformamide (9.21 mL, 119.4 mmol).After stirring at room temperature for 1 hour, saturated aqueousammonium chloride was added, and the mixture was extracted with diethylether. The organic layer was dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel to yield4-t-butyldiphenylsiloxy-2,6-dimethoxybenzaldehyde as a colorlesscrystalline powder (melting point: 177.5-120.0-C) (6.77 g, yield: 41%).

Sodium borohydride (519.0 mg, 13.73 mmol) was added to an ice-coldsolution of 4-t-butyldiphenylsiloxy-2,6-dimethoxybeenzaldehyde (3.85 g,9.15 mmol) in tetrahydrofuran (40 mL), and the mixture was stirred atroom temperature for 2 hours and 30 minutes. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to afford crude4-t-butyldiphenylsiloxy-2,6-dimethoxybenzyl alcohol as a colorlesscrystalline powder (melting point: 127.5-129.0° C.) (4.01 g).

To a solution of the crude 4-t-butyldiphenylsiloxy-2,6-dimethoxybenzylalcohol (4.01 g) obtained by the above-described procedure in anhydrousdimethylformamide (30 mL) were added imidazole (1.29 g, 18.98 mmol) andt-butylchlorodimethylsilane (1.79 g, 11.86 mmol). After stirring at 50°C. for 4 hours, water was added and the resulting mixture was extractedwith ethyl acetate-hexane (1:2). The organic layer was washed withwater, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to yield crude4-(t-butyldimethylsiloxy)methyl-1-t-butyldiphenylsiloxy-3;5-dimethoxybenzenewas obtained as a colorless amorphous powder (5.33 g).

To a solution of the crude4-(t-butyldimethylsiloxy)-methyl-1-t-butyldiphenylsiloxy-3,5-dimethoxybenzene(5.33 g) obtained by the above-described procedure in tetrahydrofuran(60 mL) was added a 1.0. M solution of tetrabutylammonium fluoride intetrahydrofuran (9.9 mL, 9.9 mmol). After stirring at room temperaturefor 5 minutes, brine was added and the mixture was extracted with ethylacetate. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel to yield4-(t-butyldimethylsiloxy)methyl-3,5-dimethoxyphenol as a colorlessamorphous powder (1.93 g, yield: 75% based on.4-t-butyldiphenylsiloxy-2,6-dimethoxybenzaldehyde).

Following the procedure of Reference Example 3, the title compound wasobtained as a colorless amorphous powder from4-(t-butyldimethylsiloxy)methyl-3,5-dimethoxyphenol(1.93 g, 6.79mmol)(1.57 g, yield: 54%).

REFERENCE EXAMPLE 13 4-Ethoxycarbonyl-1-iodo-3,5-dimethoxybenzene

To a solution of 4-iodo-2,6-dimethoxybenzoic acid (603.0 mg, 1.96 mmol),synthesized by the process described in Reference Example 11, inmethylene chloride (12 mL) were added dimethylformamide (0.020 mL, 0.26mmol) and oxalyl chloride (0.26 mL, 3.0 mmol). After stirring at roomtemperature for 30 minutes, the resulting solution was poured into anice-cold solution of triethylamine (0.50 mL, 3.6 mmol) in ethanol (10mL). The reaction mixture was stirred at room temperature for 30 minutesand concentrated under reduced pressure. A solution of the residue indiethyl ether was washed successively with water, 0.1 M hydrochloricacid and brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel to yield the title compound as a colorlessoil (641.0 mg, yield: 97%).

REFERENCE EXAMPLE 14 4-t-Butoxycarbonyl-3,5-dimethoxyphenylboronic Acid

Following the procedure described in Reference Example 13, crude4-t-butoxycarbonyl-1-iodo-3,5-dimethoxybenzene was obtained as acolorless amorphous powder (2.33 g) from 4-iodo-2,6-dimethoxybenzoicacid (2.40 g, 7.79 mmol).

Following the procedure of Reference Example 2, an oil was obtained fromthe crude 4-t-butoxycarbonyl-1-iodo-3,5-dimethoxybenzene (1.99 g,approx. 5.48 mmol) obtained by the above-described procedure. Diethylether-hexane was added to the oil and the resulting precipitate wascollected by filtration to yield the title compound as a colorlesscrystalline powder (melting point: >300.0° C.) (1.06 g, yield: 56% basedon 4-iodo-2,6-dimethoxybenzoic acid).

REFERENCE EXAMPLE 15 4-Acetyl-3,5-dimethoxyphenyltrifluoromethanesulfonate

Under nitrogen, a solution of the1-t-butyldiphenylsiloxy-3,5-dimethoxybenene (7.85 g, 22.0 mmol), whichhad been synthesized by the process described in Reference Example. 12,in anhydrous diethyl ether (80 mL) was stirred in an ice bath, and a1.59 M solution of n-butyl lithium in hexane (16.6 mL, 26.6 mmol) wasadded. After the reaction mixture was stirred at 35° C. for 1 hour and30 minutes, it was again stirred in the ice bath, then acetyl chloride(2.34 mL, 33.0 mmol) was added. After stirring at room temperature for30 minutes, saturated aqueous ammonium chloride was added, and themixture was extracted with diethyl ether. The organic., layer was washedwith water, dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel to yield4-t-butyldiphenylsiloxy-2,6-dimethoxyacetophenone as a colorless oil(2.07 g, yield: 22%).

To a solution of 4-t-butyldiphenylsiloxy-2,6-dimethoxyacetophenone (2.07g, 4.76 mmol) in tetrahydrofuran (42 mL) was added a 1.0 M solution oftetrabutylammonium fluoride in tetrahydrofuran (5.2 mL, 5.2 mmol). Thereaction mixture was stirred at room temperature for 5 minutes andconcentrated under reduced pressure. A solution of the residue inmethylene chloride (63 mL) was stirred in a dry ice-methanol bath. Afterthe addition of N,N-diisopropylethylamine (2.1 mL, 12′ mmol),trifluoromethanesulfonic anhydride (1.2 mL, 7.1 mmol) was addeddropwise. The reaction mixture was stirred for 30 minutes in the dryice-methanol bath, washed with 1.0 M hydrochloric acid and brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel to yieldthe title compound as a colorless oil (11.21 g, yield: 78%).

EXAMPLE 1 1,4-Bis(5-phenyl-2-pyridyl)hexahydro-1,4-diazepine

Under nitrogen, to a solution of the1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (200 mg, 0.585 mmol)synthesized in Reference Example 1 in ethanol-toluene (2.0 mL-2.0 mL)were added phenylboronic acid (130.0 mg, 1.07 mmol),tetrakis(triphenylphosphine)palladium (56.0 mg, 0.050 mmol) and a 2.0 Maqueous potassium carbonate (0.5 mL, 1.0 mmol), and the resultingmixture was stirred at 80° C. for 3 hours. After cooling, the organiclayer was collected and the aqueous layer was extracted with chloroform.The organic layers were combined dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel to yield crude crystals. The crudecrystals were recrystallized from chloroform-hexane to yield the titlecompound as slightly yellow needles (melting point: 221.0-222.0° C.)(61-0.0 mg, yield: 31%).

¹H-NMR (CDCl₃) δ: 2.17 (tt, J=6.3, 6.3 Hz 2H), 3.65 (dd, J=6.3, 6.3 Hz,4H), 3.96 (s, 4H), 6.64 (d, J=8.8 Hz, 2H), 7.30 (t, J=7.3 Hz, 2H), 7.42(t, J=7.3 Hz; 4H), 7.52 (d, J=17.3 Hz, 4H), 7.70 (dd, J 2.4, 8.8 Hz,2H), 8.43(d, J=2.4 Hz, 2H).

EXAMPLE 2 1,4-Bis[5-(2-methoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol)synthesized in Reference Example 1 and 2-methoxyphenylboronic acid (I82.0 mg, 1.20 mmol). The crude crystals were recrystallized frommethylene chloride-hexane to yield the title compound as slightly yellowneedles (melting point: 161.0-162.0° C.) (215.0 mg, yield: 920/o).

¹H-NMR (CDCl₃) δ: 2.16 (tt, J=6.0, 6.0 Hz, 2H), 3.64 (dd, J=6.0, 6.6 Hz,4H), 3.83 (s, 6H), 3.95 (s, 4H), 6.60 (d, J=8.7 Hz, 2H), 6.65-7.06 (m,4H), 7.28-7.33 (m, 4H), 7.69 (dd, J=2.4, 8.7 Hz, 2H), 8.36 (d, J=2.4 Hz,2H).

EXAMPLE 3 1,4-Bis[5-(3-methoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500mmol)-synthesized in Reference Example 1 and 3-methoxyphenylboronic acid(182.0 mg, 1.20-mmol). The crude crystals were recrystallized frommethylene chloride-hexane to yield the title compound as slightly yellowflakes (melting point: 146.0-149.0-C) (121.0 mg, yield: 520/o).

¹H-NMR (CDCl₃) δ: 2.16 (tt, J=6.0, 6.0 Hz, 2H), 3.63 (dd, J=6.0, 6.0 Hz,4H), 3.85 (s, 6H), 3.95 (s, 4H), 6.62 (d, J=8.7 Hz, 2H), 6.84 (ddd,J=1.9, 2.4, 8.0 Hz, 2H), 7.05 (dd, J=1.9, 2.4 Hz, 2H), 7.15 (ddd, J=2.4,2.4, 7.8 Hz, 2H), 7.33 (dd, J=7.8, 8.0 Hz, 2H), 7.68 (dd, J=2.4, 8.7 Hz,2 H), 8.42 (d, =2.4 Hz, 2H).

EXAMPLE 4 1,4-Bis[5-(4-methoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol)synthesized in Reference Example 1 and 4-methoxyphenylboronic acid(182.0 mg, 1.20 mmol). The crude crystals were recrystallized fromchloroform-hexane to yield the title compound as pale yellow needles(melting point: 254.0-256.0° C.) (98.0 mg, yield: 42%).

¹H-NMR (CDCl₃) δ: 2.16 (tt, J=6.0, 6.0 Hz, 2H), 3.62 (dd, J=6.0, 6.0 Hz,4H), 3.84 (s, 6H), 3.94 (s, 4H), 6.61 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.7Hz, 4H), 7.43 (d, J=8.7 Hz, 4H), 7.64 (dd, J=2.4, 8.7 Hz, 2H), 8.37 (d,J=2.4 Hz, 2H).

EXAMPLE 51,4-Bis[5-(4-methylthiophenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained fromthe 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500mmol) synthesized in Reference Example 1 and 4-methylthiophenylboronicacid (202.0 mg, 1.20 mmol). The crude crystals were recrystallized fromchloroform-hexane to yield the title compound as pale yellow needles(melting point: 252.0-255.0° C.) (109.0 mg, yield: 43%).

¹H-NMR (CDCl₃) δ: 2.16 (tt, J=6.0, 6.0 Hz, 2H), 2.51 (s, 6H), 3.63 (dd,J=6.0, 6.0 Hz, 4H), 3.94 (s, 4H), 6.61 (d, J=8.7 Hz, 2H), 7.31 (d, J=8.2Hz, 4H, 7.43 (d, J=8.2 Hz, 4H), 7.66 (dd, J=2.4, 8.7 Hz, 2H), 8.40 (d,J=2.4 Hz, 2H).

EXAMPLE 6 1,4-Bis[5-(4-methylphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained fromthe 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500mmol) synthesized in Reference Example 1 and 4-methylphenylboronic acid(163.0 mg, 1.20 mmol). The crude crystals were recrystallized fromchloroform-hexane to yield the title compound as pale yellow needles(melting point: 245.0-247.0° C.)(93.0 mg, yield: 42%).

¹H-NMR (CDCl₃) δ: 2.16 (tt, J=6.0, 6.0 Hz, 2H), 2.38 (s, 6H), 3.63 (dd,J=6.0, 6.0 Hz, 4H), 3.94 (s, 4H), 6.62 (d, J=8.7 Hz, 2H), 7.22 (d, J=8.0Hz, 4H), 7.41 (d, J=8.0 Hz, 4H), 7.67 (dd, J=2.4, 8.7 Hz, 2H), 8.40 (d,J=2.4 Hz, 2H).

EXAMPLE 7 1,4-Bis[5-(4-t-butylphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained fromthe 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500mmol) synthesized in Reference Example 1 and 4-t-butylphenylboronicacid: (226.0 mg, 1.20 mmol). The crude crystals were recrystallized fromchloroform-hexane to yield the title compound as colorless needles(melting point: 268.0-270.0° C.) (117.0-mg, yield: 42%).

¹H-NMR (CDCl₃) δ: 1.35 (s, 18H), 2.17 (tt, J=6.0, 6.0 Hz, 2H), 3.64 (dd,J=6.0, 6.0 Hz, 4H), 3.96 (s, 4H), 6.63 (d, J=8.7 Hz, 2H), 7.45 (s, 8H),7.67 (dd, J=2.4, 8.7 Hz, 2H), 8.42 (d, J=2.4 Hz, 2H).

EXAMPLE 81,4-Bis[5-(4-trifluoromethylphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained fromthe 1,4-bis(5-bromo-2-pyridyl)hexahydro-11,4-diazepine (206.0 mg, 0.500mmol) synthesized in Reference Example 1 and4-trifluoromethylphenylboronic acid (227.0 mg, 1.20 mmol). The crudecrystals were recrystallized from chloroform-hexane to yield the titlecompound as colorless needles (melting point: 236.0-238.0° C.) (110.0mg, yield: 40%).

¹H-NMR (CDCl₃) δ: 2.16 (tt, J=6.0, 6.0 Hz, 2H), 3.66 (dd, J=6.0, 6.0 Hz,4H), 3.97 (s, 4H), 6.65 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.5 Hz, 4H), 7.66(d, J=8.5 Hz, 4H), 7.70 (dd, J=2.4, 8.7 Hz, 2H), 8.43 (d, =2.4 Hz, 2H).

EXAMPLE 9 1,4-Bis[5-(4-fluorophenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-4-diazepine (206.0 mg, 0.500 mmol)synthesized in Reference Example 1 and 4-fluorophenylboronic acid (168.0mg, 1.20 mmol). The crude crystals were recrystallized fromchloroform-hexane to yield the title compound as colorless needles(melting point: 268.0-270.0° C.) (115.0 mg, yield: 52%).

¹H-NMR (CDCl₃) δ: 2.16 (tt, J=6.0, 6.0 Hz, 2H), 3.64 (dd, J=6.0, 6.0 Hz,4H), 3.95 (s, 4H), 6.62 (d, J=8.7 Hz, 2H), 7.10 (dd, J=8.7 Hz,³J_(HF)=8.7 Hz, 4H), 7.45 (dd, J=8.7 Hz, ⁴J_(HF)=5.3 Hz, 4H), 7.63 (d,J=2.4, 8.7 Hz, 2H), 8.36 (d, J=2.4 Hz, 2H).

EXAMPLE 10 1,4-Bis[5-(4-chlorophenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol)and 4-chlorophenylboronic acid (188.0 mg, 1.20 mmol). The crude crystalswere recrystallized from chloroform-hexane to yield the title compoundas colorless needles (melting point: 245.0-247.0° C.) (105.0 mg, yield:

¹H-NMR (CDCl₃) δ: 2.15 (tt, J=6.0, 6.0 Hz; 2H), 3.63 (dd, J=6.0, 6.0 Hz,4H), 3.95 (s, 4H), 6.62 (d, J=8.7 Hz, 2H), 7.37 (d, J=8.2 Hz, 4H), 7.43(d, J=8.2 Hz, 4H), 7.64 (dd, J=2.4, 8.7 Hz, 2H), 8.38 (d, J=2.4 Hz, 2H).

EXAMPLE 111,4-Bis[5-(2,3-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinedimethanesulfonate

Following the procedure of Example 1,1,4-bis[5-(2,3-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine wasobtained as a colorless oil (28.0 mg, yield: 26%) from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (82.0 mg, 0.200 mmol)synthesized in Reference Example 1 and 2,3-dimethoxyphenylboronic acid(Bull. Soc. Chim. Fr., 767-769 (1973)) (146.0 mg, 0.800 mmol)synthesized in a similar manner to that described in Reference Example2.

To a solution of1,4-bis[5-(2,3-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine (28.0mg, 0.053 mmol) in chloroform (3.0 mL) was added a 1.0 M solution ofmethane-sulfonic acid in methanol (0.11 mL, 0.11 mmol), and the reactionmixture was concentrated under reduced pressure. The residue wasrecrystallized from methylene chloride-methanol-diethyl ether to yieldthe title compound as a pale brown crystalline powder (melting point:199.5-202.0° C.) (32.3 mg, yield: 86%).

¹H-NMR (CDCl₃) (ammonium salt NH⁺ protons were not observed) δ:1.85-2.43 (m, 2H), 2.90 (s, 6H), 3.69 (s, 6H), 3.90 (s, 6H), 3.95-4.10(m, 4H), 4.31 (s, 4H), 6;88 (br.d, J=6.0 Hz, 2H), 6.97 (br.d, J=6.0 Hz,2H), 7.11 (br.dd, J=6.0 Hz, 6.0 Hz, 2H), 7.26 (br.d, J=7.6 Hz, 2H), 8.20(br.d, J=7.6 Hz, 2H), 8.35 (br.s, 2H).

EXAMPLE 121,4-Bis[5-(2,4-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol)synthesized in Reference Example 1 and 2,4-dimethoxyphenylboronic acid(218.0 mg, 1.20 mmol). The crude crystals were recrystallized fromchloroform-hexane to yield the title compound as colorless needles(melting point: 161.0-163.0° C.)(206.0-mg, yield: 78%).

¹H-NMR (CDCl₃) δ: 2.15 (tt, J=6.0, 6.0 Hz, 2H), 3.63 (dd, J=6.0, 6.0 Hz,4H), 3.80 (s, 6H), 3.84 (s, 6H), 3.93 (s, 4H), 6.54-6.57 (m, 4H), 6.58(d, J=8.7 Hz, 2H), 7.21 (d, J=9.0 Hz, 2H), 7.64 (dd, J=2.4, 8.7 Hz, 2H),8.30 (d, J=2.4 Hz, 2H).

EXAMPLE 131,4-Bis[5-(2,6-dimethoxyphenyl)-2pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, an oil was obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (I 00.0 mg, 0.240mmol) synthesized in Reference Example 1 and 2,6-dimethoxyphenylboronicacid (Chem. Abs., 123, pr256679r.) (150.0 mg, 1.00 mmol).Methanol-chloroform-hexane was added to the oil, and the resultingprecipitate was collected by filtration to yield the title compound as apale yellow crystalline powder (melting point: ≧300° C.) (24.0 mg,yield: 19%).

¹H-NMR [CD₃OD-CDCl₃(1:10)] δ: 2.16 (tt, J=6.1, 6.1 Hz, 2H), 3.67 (dd,J=6.1, 6.1 Hz, 4H), 3.77 (s, 12H), 3.92 (s, 4H), 6.64 (d, J=8.7 Hz, 2H),6.66 (d, J=8.5 Hz, 4H), 7.26 (t, J=8.5 Hz, 2H), 7.54 (dd, J=2.2, 8.7 Hz,2H), 8.15 (d, J=2.2 Hz, 2H).

EXAMPLE 141,4-Bis[5-(3,4-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example I, crude crystals were obtained from−1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500mmol) synthesized in Reference Example 1 and 3,4-dimethoxyphenylboronicacid (2-1.8.0 mg, 1.20 mmol). The crude crystals were recrystallizedfrom chloroform-hexane to yield the title compound as pale yellowneedles (melting point: 190.0-192.0° C.) (129.0 mg, yield: 48%).

¹H-NMR (CDCl₃) δ: 2.16 (tt, J=6.0, 6.0 Hz, 2H), 3.63 (dd, J=6.0, 6.0 Hz,4H), 3.91 (s, 6H), 3.93 (s, 6H), 3.95 (s, 4H), 6.62 (d, J=8.7 Hz, 2H),6.93 (d, J=8.2 Hz, 2H), 7.02 (d, J=1.9 Hz, 2H), 7.05 (dd, J=1.9, 8.2 Hz,2H), 7.65 (dd, J=2.4, 8.7 Hz, 2H), 8.39 (d, J=2.4 Hz, 2H).

EXAMPLE 151,4-Bis[5-(3,4-methylenedioxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol)synthesized in Reference Example 1 and 3,4-methylenedioxyphenylboronicacid (199.0 mg, 1.20 mmol). The crude crystals were recrystallized fromchloroform-hexane to yield the title compound as pale yellow needles(melting point: 235.0-237.0° C.) (105.0 mg, yield: 42%).

¹H-NMR (CDCl₃) δ: 2.15 (tt, J=6.0, 6.0 Hz, 2H), 3.62 (dd, J=6.0, 6.0 Hz,4H), 3.93 (s, 4H), 5.98 (s, 4H), 6.59 (d, J=8.7 Hz, 2H), 6.86 (d, J=8;0Hz, 2H), 6.95 (dd, J=1.7, 8.0 Hz, 2H), 6.98 (d, J=1.7 Hz, 2H), 7.60 (dd,J=2.4, 8.7 Hz, 2H), 8.32 (d, J=2.4 Hz, 2H).

EXAMPLE 161,4-Bis[5-(3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinedimethanesulfonate

Following the procedure of Example 1,1,4-bis[5-(3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine wasobtained as a colorless oil (89.0 mg, yield: 71%) from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (100.0 mg, 0.240 mmol)synthesized in Reference Example 1 and 3,5-dimethoxyphenylboronic acid(79.0 mg, 0.530 mmol) synthesized in a similar manner to that describedin Reference Example 2.

To a solution of1,4-bis[5-(3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine (89.0mg, 0.170 mmol) in methanol (5.0 mL) was added a 1.0 M aqueousmethanesulfonic acid (0.34 mL, 0.34 mmol), and the reaction mixture wasconcentrated under reduced pressure. Ethanol (5.0 mL) was added to theresidue, and the resulting mixture was concentrated under reducedpressure. The residue was recrystallized from methanol-diethyl ether toyield the title compound as a pale yellow crystalline powder (meltingpoint: 181.0-183.0° C.) (81.0 mg, yield: 66%).

¹H-NMR (CDCl₃) (ammonium salt NH⁺ protons were not observed) δ:2.35-2.45 (m, 2H), 2.91 (s, 6H), 3.81 (s, 12H), 3.95-4.10 (m, 4H), 4.31(s, 4H), 6.47 (t, J=2.2 Hz, 2H), 6.55 (d, J=2.2 Hz, 4H), 7.34 (d, J=9.6Hz, 2H), 8.12 (dd, J=2.2, 9.6. Hz, 2H), 8.36 (d, J=2.2 Hz, 2H).

EXAMPLE 171,4-Bis[5-(3,5-diethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Under nitrogen, to a solution of 3,5-diethoxyphenyltrifluoromethanesulfonate (WO99/41224) (251.0 mg, 0.800 mmol) indimethylformamide (6.5 mL) were added bis(pinacolato)diboron (223.0 mg,0.880 mmol),dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II)dichloromethane complex (1.1) (19.6 mg, 0.024 mmol),1,1′-bis(diphenylphosphino)ferrocene (13.3 mg, 0.024 mmol) and potassiumacetate (236.0 mg, 2.40 mmol), and the resulting mixture was stirred at80° C. for 12 hours. To the reaction mixture were added0,1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (110.0 mg, 0.270mmol) synthesized by the process described in Reference Example 1,dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(I)dichloromethane complex (1:1) (19.6 mg, 0.024 mmol) and a 2.0 M sodiumcarbonate (2.0 mL, 4.0 mmol). The resulting mixture was stirred at 80°C. for 1 hour. Water was added to the reaction mixture, and the mixturewas extracted with diethyl ether. The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to yield thetitle compound as a colorless amorphous powder (70.0 mg, yield: 45%).

¹H-NMR (CDCl₃) δ: 1.43 (t, J=7.0 Hz, 12H), 2.16 (tt, J=6.2, 6.2 Hz, 2H),3.63 (dd, J=6.2, 6.2 Hz, 4H), 3.94 (s, 4H), 4.06 (q, J=7.0 Hz, 8H), 6.40(t, J=2.2 Hz, 2H), 6.60 (d, J=8.9 Hz, 2H), 6.64 (d, J=2.2 Hz, 4H), 7.66(dd, J=2.6, 8.9 Hz, 2H), 8.41 (d, J=2.6 Hz, 2H).

EXAMPLE 181,4-Bis[5-(3,5-diisopropoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 17, an oil was obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (103.0 mg, 0.250 mmol)synthesized in Reference Example 1 and 3,5-diisopropoxyphenyltrifluoromethanesulfonate (261.0 mg, 0.760 mmol) synthesized inReference Example 3. Hexane was added to the oil, and the resultingprecipitate was collected by filtration to yield the title compound as acolorless crystalline powder (melting point: 131.0-132.0° C.) (78.0 mg,yield: 49%).

¹H-NMR (CDCl₃) 5:1.36 (d, J=, 6.0 Hz, 24H), 2.16 (tt, J=6.2, 6.2 Hz,2H), 3.63 (dd, J=6.2, 6.2 Hz, 4H), 3.94 (s, 4H), 4.57 (qq, J=6.0, 6.0Hz, 4H), 6.39 (t, J=2.3 Hz, 2H), 6.60 (d, J=8.9 Hz, 2H), 6.62 (d, J=2.3Hz, 4H), 7.66 (dd, J=2.6, 8.9 Hz, 2H), 8.40 (d, J=2.6 Hz, 2H).

EXAMPLE 191,4-Bis[5-(3,5-dimethylphenyl)-2-pyridyl]hexahydro-1,4-diazepinedimethanesulfonate

Following the procedure of Example 1,1,4-bis[5-(3,5-dimethylphenyl)-2-pyridyl]hexahydro-1,4-diazepine wasobtained as a yellow crystalline powder (83.0 mg, yield: 89%) from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (82.0 mg, 0.200 mmol)synthesized in Reference Example 1 and 3,5-dimethylphenylboronic acid(90.0 mg, 0.600 mmol).

To a solution of1,4-bis[5-(3,5-dimethylphenyl)-2-pyridyl]hexahydro-1,4-diazepine (83.0mg, 0.170 mmol) in methanol (5.0 mL) was added a 1.0 M aqueousmethanesulfonic acid (0.37 mL, 0.37 mmol), and the mixture wasconcentrated under reduced pressure. Ethanol (5.0 mL) was added to theresidue, and the resulting mixture was concentrated under reducedpressure. The residue was recrystallized from ethanol-diethylether-hexane to yield the title compound as colorless needles [meltingpoint: 188.0° C. (decomposed)](101.0 mg, yield: 86%).

¹H-NMR (DMSO-d₆, 120° C.)(ammonium salt NH⁺protons were not observed) δ:2.02 (tt, J=5.8, 5.8 Hz, 2H), 2.28 (s, 12H), 2.46 (s, 6H), 3.78 (dd, J5.8, 5.8 Hz, 4H), 4.01 (s, 4H), 6.94 (br.s, 2H), 6.99 (d, J=9.2 Hz, 2H),7.09 (br.s, 4H), 7.88 (dd, J=2.4, 9.2 Hz, 2H), 8.19 (d, J=2.4. Hz, 2H).

EXAMPLE 201,4-Bis[5-[3,5-bis(methoxycarbonyl)phenyl]-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 17, an oil was obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (207.8 mg, 0.504 mmol)synthesized in Reference Example 1 and 3,5-bis(methoxycarbonyl)phenyltrifluoromethanesulfonate (J. Org. Chem., 65, 5360-5370 (2000)) (474.4mg, 1.39 mmol). Diethyl ether was added to the oil, and the resultingprecipitate was collected by filtration to yield the title compound as acolorless crystalline powder (melting point: 216.0-217.5° C.) (92.8 mg,yield: 10%).

¹H-NMR (CDCl₃) δ: 2.17 (tt, J=6.1, 6.1 Hz, 2H), 3;66 (dd, J=6.1, 6.1 Hz,4H), 3.97 (s, 12H), 3.98 (s, 4H), 6.66 (d, J=8.9 Hz, 2H), 7.76 (dd,J=2.5, 8.9 Hz, 2H), 8.38 (d, J=1.1 Hz, 4H), 8.49 (d, J=2.5 Hz, 2H), 8.58(t, J=1.1 Hz, 2H).

EXAMPLE 211,4-Bis[S-[3,5-bis(hydroxymethyl)phenyl]-2-pyridyl]hexahydro-1,4-diazepine

Under nitrogen, a solution of1,4-bis[5-[3,5-bis(methoxycarbonyl)phenyl]-2-pyridyl]hexahydro-1,4-diazepine(17.0 mg, 0.0266 mmol), which had been synthesized in Example 20, inanhydrous tetrahydrofuran (1.0 mL) was cooled to −20° C. To theresulting solution was added a 1.0 M solution of diisobutylaluminumhydride in toluene (0.40 mL, 0.40 mmol), and the resulting mixture wasstirred for 1 hour. Methanol (0.2 mL, 4.9 mmol) was added to themixture, and the bath was removed, then 0.50 M hydrochloric acid (1.0mL, 0.50 mmol) was added. The mixture was stirred at room temperaturefor 1 hour, and a 1.0 M aqueous sodium hydroxide (1.0 mL, 1.0 mmol) andbrine were added. The resulting mixture was extracted with chloroform,and the organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified bypreparative thin-layer chromatography on silica gel to yield the titlecompound as a colorless amorphous powder (7.4 mg, yield: 53%).

¹H-NMR (CD₃OD) δ: 2.31 (tt, J=5.9, 5.9 Hz, 2H), 3.86 (dd, J=5.9, 5.9 Hz,4H), 4.14 (s, 4H), 4.83 (s, 8H), 6.98 (d, J=8.9 Hz, 2H), 7.46 (br.s,2H), 7.60 (br.s, 4H), 7.97 (dd, J=2.3, 8.9 Hz, 2H), 8.51 (d, J=2.3 Hz,2H).

EXAMPLE 22 1,4-Bis[5-[3,5bis(methoxymethyl)phenyl]-2-Pyridyl]hexahydro-1,4-diazepinedihydrochloride

Following the procedure of Example 17,1,4-bis[57[3,5-bis(methoxymethyl)-phenyl]72-pyridyl]hexahydro-1,4-diazepinewas obtained as a colorless oil (51.9 mg, yield: 33%) from1,4-bis(5$bromo-2-pyridyl)hexahydro-1,4-diazepine (99.5 mg, 0.242 mmol)synthesized in Reference Example 1 and 3,5-bis(methoxymethyl)phenyltrifluoromethanesulfonate (171.0 mg, 0.545 mmol) synthesized inReference Example 4.

To a solution of1,4-bis[5-[3,5-bis(methoxymethyl)phenyl]-2-pyridyl]hexahydro-1,4-diazepine(51.9 mg, 0.0892 mmol) in ethanol (5.0 mL) was added 10.0 M hydrochloricacid (0.21 mL, 0.21 mmol), and the reaction mixture was concentratedunder reduced pressure. Ethanol (5.0 mL) was added to the residue andthe resulting mixture was concentrated under reduced pressure to yieldthe title compound as a colorless amorphous powder (47.8 mg, yield:92%).

¹H-NMR (CDCl₃) (ammonium salt NH⁺ protons were not observed) δ:2.36-2.50 (m, 2H), 3.42 (br.s, 12H), 4.02-4.22 (m, 4H), 3.96-4.52 (m,4H), 4.48 (br.s, 8H), 7.14-7.32 (m, 2H), 7.33 (br.s, 2H), 7.39 (br.s,4H), 8.09-8.12 (m, 2H), 8.38-8.44 (m, 2H).

EXAMPLE 231,4-Bis[5-(2,4,6-trimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, an oil was obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-4-diazepine (120.0 mg, 0.290 mmol)synthesized in Reference Example 1 and 2,4,6-trimethoxyphenylboronicacid (Tetrahedron Lett., 32, 2229-2232 (1991)) (304.0 mg, 1.45 mmol).Chloroform-hexane was added to the oil, and the resulting precipitatewas collected by filtration to yield the title compound as a yellowcrystalline powder (melting point: 243.0-247.0° C.) (29.0 mg, yield:17%).

¹H-NMR (CDCl₃) δ: 2.16 (tt, J=6.1, 6.1 Hz, 2H), 3.65 (dd, J=6.1, 6.1 Hz,4H), 3.75 (s, 12H), 3.86 (s, 6H), 3.93 (s, 4H), 6.23 (s, 4H), 6.59 (d,J=8.8 Hz, 2H), 7.48 (dd, J=. 2.2, 8.8 Hz, 2H), 8.17 (d, J=2.2 Hz, 2H).

EXAMPLE 241,4-Bis[5-(2,3,4-trimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, an oil was obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (115.0 mg, 0.280-mmol)synthesized in Reference Example 1 and 2,3,4-trimethoxyphenylboronicacid (130.0 mg, 0.620 mmol) synthesized from 2,3,4-trimethoxybromobenzne(J. Org. Chem., 23, 16-17 (1958)) in a similar manner as in ReferenceExample 2. Chloroform-hexane was added to the oil, and the resultingprecipitate was collected by filtration to yield the title compound as ayellow crystalline powder (melting point: 192.0-194.0° C.) (57.0 mg,yield: 35%).

¹H-NMR (CDCl₃) δ: 2.17 (tt, J=6.1, 6.1 Hz, 2H), 3.65 (dd, J=6.1, 6.1 Hz,4H), 3.72 (s, 6H), 3.89 (s, 6H), 3.92 (s, 6H), 3.96 (s, 4H), 6.60 (d,J=8.8 Hz, 2H), 6.73 (d, J=8.5 Hz 2H), 7.00 (d, J=8.5 Hz, 2H), 7.67 (ddJ=2.4, 8.8 Hz, 2H), 8.28 (d, J=2.4 Hz, 2H).

EXAMPLE 251,4-Bis[5-(2,3,5-trimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, an oil was obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (109.0 mg, 0.264 mmol)synthesized in Reference Example 1 and 2,3,5-trimethoxyphenylboronicacid (140.0 mg, 0.660 mmol) synthesized from1-bromo-2,3,5-trimethoxybenzene (J. Am. Chem., 61, 144-147 (1939)) in asimilar manner to that described in Reference Example 2.Methanol-diethyl ether was added to the oil, and the resultingprecipitate was collected by filtration to yield the title compound as apale brown crystalline powder (melting point: 155.0-160.0° C.) (15.0 mg,yield: 10%).

¹H-NMR (CDCl₃) δ: 2.13-2.23 (m, 2H), 3.56 (s, 6H), 3.64-3.70 (m, 4H),3.81 (s, 6H), 3.88 (s, 6H), 3.97 (s, 4H), 6.43 (d, J=2.7 Hz, 2H), 6.48(d, J=2.7 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 7.76 (dd, J=2.2, 9.0 Hz, 2H),8.37 (d, J=2.2 Hz, 2H).

EXAMPLE 261,4-Bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]hexahydro-4-diazepinedimethanesulfonate

Following the procedure of Example 1,1,4-bis[5-(3,4,5-triethoxylphenyl)-2-pyridyl]hexahydro-1,4-diazepine wasobtained as a colorless oil (22.6 mg, yield: 53%) from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (30.0 mg, 0.0730 mmol)synthesized in Referenced Example 1 and 3,4,5-triethoxylphenylboronicacid (45.4 mg, 0.214 mmol).

To a solution of1,4-bis[5-(3,4,5-triethoxylphenyl)-2-pyridyl]hexahydro-1,4-diazepine(72.4 g, 0.120 mol) in ethanol-chloroform (1:3, 600 mL) was addedmethanesulfonic acid (24.9 g, 0.258 mol), and the reaction mixture wasconcentrated under reduced pressure. The residue was recrystallized frommethanol-diethyl ether to yield the title compound as a slightly yellowcrystalline powder (melting point: 204.0-206-0° C.) (88.2 g, yield:92%).

¹H-NMR (DMSO-d₆, 120° C.) (ammonium salt NH⁺ protons were not observed)δ: 1.95-2.05. (m, 2H), 2.42 (s, 6 Hz), 3.72 (s, 6H), 3.74-3.77 (m, 4H),3.82 (s, 12H), 3.98 (s, 4H), 6.79 (s, 4H), 6.92 (d, J=9.0 Hz, 2H), 7.88(dd, J=2.4, 9.0 Hz, 2H), 8.26 (d, J=2.4 Hz, 2H).

EXAMPLE 271,4-Bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinedimethanesulfonate

Following the procedure of Example 1,1,4-bis[5-(3,4,5-triethoxylphenyl)-2-pyridyl]hexahydro-1,4-diazepine wasobtained as a colorless oil (77 mg, yield: 48%) from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (100.0 mg, 0.240 mmol)synthesized in Reference Example 1 and 3,4,5-triethoxylphenylboronicacid (134.0 mg, 0.530 mmol) synthesized in Reference Example 5.

To a solution of1,4-bis[5-(3,4,5-triethoxylphenyl)-2-pyridyl]hexahydro-1,4-diazepine (77mg, 0.115 mmol) in methanol (5.0 mL) was added a 1.0 M aqueousmethanesulfonic acid (0.23 mL, 0.23 mmol), and the reaction mixture wasconcentrated under reduced pressure. Ethanol (5.0 mL) was added to theresidue, and the resulting mixture was concentrated under reducedpressure. The residue was recrystallized from methanol-diethyl ether toyield the title compound as a pale yellow crystalline powder (meltingpoint: 235.0-237.0° C.) (74.0 mg, yield: 94%).

¹H-NMR (DMSO-d₆, 120° C.)(ammonium salt NH⁺ protons were not observed)δ: 1.26 (t, J=7.1 Hz, 6H), 1.33 (t, J=7.1 Hz, 12H), 2.01 (tt, J=5.9, 5.9Hz, 2H) 2.40 (s, 6H), 3.74 (dd, J=5.9, 5.9 Hz, 4H), 3.96 (s, 4H), 3.99(q, J=7.1 Hz, 4H), 4.08 (q, J=7.1 Hz, 8H), 6.75 (s, 4H), 6.88 (d, J=9.5Hz, 2H), 7.83 (dd, 3=2.4, 9.5 Hz, 2H), 8.23 (d, J=2.4 Hz, 2H).

EXAMPLE 281,4-Bis[5-(3,5-diisopropoxy-4-methoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, an oil was obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (100.0 mg, 0.240 mmol)synthesized in Reference Example 1 and3,5-diisopropoxy-4-methoxyphenylboronic acid (142.0 mg, 0.530 mmol)synthesized in Reference Example 6. The oil was recrystallized fromchloroform-hexane to yield the title compound as slightly brown needles(melting point: 164.0-165.0° C.) (90.0 mg, yield: 53%).

¹H-NMR (CDCl₃) δ: 1.38 (d, J=5.9 Hz, 24H), 2.16 (tt, J=5.9, 5.9 Hz, 2H),3.63 (dd, J=5.9, 5.9 Hz, 4H), 3.85 (s, 6H), 3.95 (s, 4H), 4.57 (qq,J=5.9, 5.9 Hz, 4H), 6.61 (d, J=9.0 Hz, 2H), 6.70 (s, 4H), 7.63 (dd,J=2.4, 9.0 Hz, 2H), 8.37 (d, J=2.4 Hz, 2H).

EXAMPLE 291,4-Bis[5-(4-isopropoxy-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinedimethanesulfonate

Following the procedure of Example I, an oil was obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (100.0 mg, 0.240 mmol)synthesized in Reference Example 1 and4-isopropoxy-3,5-dimethoxyphenylboronic acid (127.0 mg, 0.530 mmol)synthesized from methyl syringate in the same manner as described inReference Example 6,1,4-bis[5-(4-isopropoxy-3,5-dimethoxy)-2-pyridyl]hexahydro-1,4-benzodiazepinewas obtained as a colorless viscous oil (107.0 mg, yield: 69%) by thesame procedure described in Example 1.

To a solution of1,4-bis[5-(4-isopropoxy-3;5-dimethoxy)-2-pyridyl]hexahydro-1,4-benzodiazepine(107.0 mg, 0.166 mmol) was added 1.0 M aqueous methanesulfonic acid(0.35 mL, 0.35 mmol), and the reaction mixture was concentrated underreduced pressure. Ethanol (5.0 mL) was added to the residue, and theresulting mixture was concentrated under reduced pressure.Methanol-diethyl ether was added to the residue, and the resultingprecipitate was collected to yield the title compound as a pale yellowcrystalline powder (melting point: 192.0-196.0° C.) (100.0 mg, yield:72%).

¹H-NMR (DMSO-d₆, 120° C.) (ammonium salt NH⁺ protons were not observed)δ: 1.21 (d, J=6.1 Hz, 12H), 2.02 (tt, J=5.9, 5.9 Hz, 2H), 2.41 (s, 6H),3.75 (dd, J=5.9, 5.9 Hz, 4H), 3.80 (s, 12H), 3.97 (s, 4H), 4.30 (qq,J=6.1, 6.1 Hz, 2H), 6.78 (s, 4H), 6.90 (d, J=9.3 Hz, 2H), 7.87 (dd,J=2.4, 9.3 Hz, 2H), 8.27 (d, J=2.4 Hz, 2H).

EXAMPLE 301,4-Bis[5-(3-methoxy-4,5-methylenedioxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinedimethanesulfonate

Following the procedure of Example 1,1,4-bis[5-(3-methoxy-4,5-methylenedioxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinewas obtained as a colorless oil (92.0 mg, yield: 71%) from0,1,4-bis(5-bromo-2-pyridyl)hexahydro 1,4-diazepine (100.0 mg, 0.240,mmol) synthesized in Reference Example 1 and3-methoxy-4,5-methylenedioxyphenylboronic acid (103.0 mg, 0.530 mmol)synthesized in Reference Example 7.

To a solution of1,4-bis[5-(3-methoxy-4,5-methylenedioxyphenyl)-2-pyridyl]hexahydro1,4-diazepine (92.0 mg, 0.170 mmol) in methanol (5.0 mL) was added a 1.0M aqueous methanesulfonic acid (0.33 mL, 0.33 mmol), and the reactionmixture was concentrated under reduced pressure. Ethanol (5.0 mL) wasadded to the residue, and the resulting mixture was concentrated underreduced pressure. Methanol-diethyl ether was added to the residue, andthe resulting precipitate was collected to yield the title compound as apale yellow crystalline powder (melting point: 212.0-215.0° C. (87.0 mg,yield: 68%).

¹H-NMR (CDCl₃)(data of free base of the title compound) δ: 2.15 (tt,J=6.1, 6.1 Hz, 2H), 3.63 (dd, J=6.1, 6.1 Hz, 4H), 3.94 (s, 4H), 3.95 (s,6H), 6.00 (s, 4H), 6.60 (d, J=8.8 Hz, 2H), 6.65 (s, 2H), 6.68 (s, 2H),7.60 (dd, J=2.4, 8.8 Hz, 2H), 8.34 (d, J=2.4 Hz, 2H).

EXAMPLE 31 1,4-Bis[5-(4-hydroxy-3,5dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1,1,4-bis[5-(4-benzyloxy-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinewas obtained as a colorless oil (61.0 mg, yield: 63% o) from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (54.0 mg, 0:130 mmol)synthesized in Reference Example 1 and4-benzyloxy-3,5-dimethoxyphenylboronic acid (80.0 mg, 0.280 mmol)synthesized in Reference Example 8.

To a solution of1,4-bis[5-(4-benzyloxy-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine(27.0 mg, 0.037 mmol) in methanol (1.0 mL) were added 10% palladium oncharcoal (14.0 mg) and ammonium formate (14.0 mg, 0.220 mmol), and theresulting mixture was stirred at 70° C. for 2 hours. Insoluble materialswere removed by filtration through Celite, and the filtrate wasconcentrated under reduced pressure. A solution of the residue inchloroform was washed with water and brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue wasrecrystallized from methanol-chloroform-diethyl ether to yield the titlecompound as pale brown needles (melting point: 200.0-202.0° C.) (17.0mg, yield: 85%).

¹H-NMR (CDCl₃) δ: 2.16 (tt, J=6.3, 6.3 Hz, 2H), 3.63 (dd, J=6.3, 6.3 Hz,4H), 3.94 (s, 12H), 3.95 (s, 4H), 5.50 (s, 2H), 6.61 (d, J=8.8 Hz, 2H),6.71 (s, 4H), 7.46 (dd, J=2.2, 8.8 Hz, 2H), 8.37 (d, J=2.2 Hz, 2H).

EXAMPLE 321,4-Bis[5-(3-hydroxy-4,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinedimethanesulfonate

The procedure described in Example 31 was employed. From1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (115.0 mg, 0.280 mmol)synthesized in Reference Example 1 and3-benzyloxy-4,5-dimethoxyphenylboronic acid (170.0 mg, 0.590 mmol)synthesized from methyl 3-hydroxy-4,5-dimethoxybenzoate (Indian J.Chem., 21B, 27-29, (1982)) by a similar procedure to that described inReference Example8,1,4-bis[5-(3-benzyloxy-4,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinewas obtained as a colorless viscous oil (173.0 mg, yield: 84%). From1,4-bis[5-(3-benzyloxy-4,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine(157.0 mg, 0.210 mmol),1,4-bis[5-(3-hydroxy-4,5-dimethoxyphenyl)-2-pyridyl]-hexahydro-1,4-diazepinewas obtained as a colorless oil (97.0 mg, yield: 84%).

To a solution of1,4-bis[5-(3-hydroxy-4,5-dimethoxyphenyl)₇₂-pyridyl]hexahydro-1,4-diazepine(97.0 mg, 0.170 mmol) in methanol (5.0 mL) was added a 1.0 M aqueousmethanesulfonic acid (0.35 mL, 0.35 mmol), and the reaction mixture wasconcentrated under reduced pressure. Ethanol (5.0 mL) was added to theresidue, and the resulting mixture was concentrated under reducedpressure. The residue was recrystallized from methanol to yield thetitle compound as a colorless crystalline powder (melting point:300.0-301.0° C.) (84.0 mg, yield: 63%).

¹H-NMR (DMSO-d₆, 120° C.) (neither ammonium salt NH⁺ protons nor phenolOH protons were observed) δ: 1.96-2.06 (m, 2H), 2.41 (s, 6H), 3.71-3.77(m, 4H), 3.73 (s, 6H), 3.81 (s, 6H), 3.97 (s, 4H), 6.62 (d, J=2.2 Hz,2H), 6.65 (d, J=2.2 Hz, 2H), 6.94 (d, J=9.3 Hz, 2H), 7.83 (dd, J=2.4,9.3 Hz, 2H), 8.17 (d, J=2.4 Hz 2H).

EXAMPLE 331,4-Bis[5-(3,5-dimethoxy-4-methylthiophenyl)-2-pyridyl]hexahydro-1,4-diazepinedimethanesulfonate

Following the procedure of Example 1,1,4-bis[5-(3,5-dimethoxy-4-methylthiophenyl)-2pyridyl]hexahydro-1,4-diazepine was obtained as a colorless oil (72.0mg, yield: 61% o) from 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine(80.0 mg, 0.192 mmol) synthesized in Reference Example 1 and3,5-dimethoxy-4-methylthiophenylboronic acid (96.0 mg, 0.422 mmol)synthesized in Reference Example 9.

To a solution of 1,4-bis[5-(3,5-dimethoxy-4methylthiophenyl)-2-pyridyl]hexahydro-1,4-diazepine (72.0 mg, 0.120mmol) in methanol (5.0 mL) was added a 1.0 M aqueous methanesulfonicacid (0.24 mL, 0.24 mmol), and the reaction mixture was concentratedunder reduced pressure. Ethanol (5.0 mL) was added to the residue, andthe resulting mixture was concentrated under reduced pressure.Methanol-diethyl ether was added to the residue, and the resultingprecipitate was collected to yield the title compound as a pale yellowcrystalline powder (melting point: 212.0-217.0° C. (58.0 mg, yield:61%).

¹H-NMR (CDCl₃)(ammonium salt NH⁺ protons were not observed) δ: 2.37-2.40(m, 2H), 2.38 (s, 6H), 2.91 (s, 6H), 3.92 (s, 12H), 4.00-4.05 (m, 4H),4.32 (s, 4H), 6.61 (s, 4H), 7.40 (d, J=9.4 Hz, 2H), 8.16 (dd, J=2.2, 9.4Hz, 2H), 8.46 (d, J=2.2 Hz, 2H).

EXAMPLE 341,4-Bis[5-(4-amino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinetetrahydrochloride

Following the procedure of Example 17,1,4-bis[57(4-benzyloxycarbonylamino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinewas obtained as a colorless oil (120.0 mg, yield: 26%) from1,4-bis(5-bromo-2-pyridyl)hexahydro-0,1,4-diazepine (228.0 mg, 0.550mmol) synthesized in Reference Example 1 and4-benzyloxycarbonylamino-1-bromo-3,5-dimethoxybenzene (450.0 mg, 1.24mmol).

To a solution of1,4-bis[5-(4-benzyloxycarbonylamino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine(120.0 mg, 0.140 mmol) in acetic acid (2.0 mL) was added 10% palladiumon charcoal (24.0 mg), and the resulting mixture was stirred at 50° C.for 1.5 hours under hydrogen. Insoluble materials were removed byfiltration through Celite, and the filtrate was concentrated underreduced pressure. A solution of the residue in chloroform was washedwith saturated aqueous sodium hydrogencarbonate and brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. To asolution of the residue in chloroform (5.0 mL) a 4.0 M solution ofhydrogen chloride in ethyl acetate (0.14 mL, 0.56 mmol), and theresulting mixture was concentrated under reduced pressure. Ethanol (5.0mL) was added to the residue, and the resulting mixture was concentratedunder reduced pressure. Diethyl ether was added to the residue, and theresulting precipitate was collected by filtration to yield the titlecompound as a pale brown amorphous powder (84.0 mg, yield: 820%).

¹H-NMR (CDCl₃)-(data of the free base of the title compound; amine NH₂protons were not observed) δ: 2.12-2.22 (m, 2H), 3.59-3.66 (m, 4H), 3.90(s, 12H), 3.9.4 (s, 4H), 6.60 (d, J=8.8 Hz, 2H), 6.67 (s, 4H), 7.64 (d,J=2.0, 8.8 Hz, 2H), 8.38 (d, J=2.0 Hz, 2H).

EXAMPLE 351,4-Bis[5-(4-dimethylamino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 17, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (210.0 mg, 0.510 mmol)synthesized in Reference Example 1 and1-bromo-4-dimethylamino-3,5-dimethoxybenzene (300.0 mg, 1.14 mmol)synthesized from 4-bromo-2,6-dimethoxyaniline (Z. Naturforsch., B24(5),524-527(1969)). The crude crystals were recrystallized from methanol toyield the title compound as a yellow crystalline powder (melting point:211.0-213.0° C.) (36.0 mg, yield: 12%).

¹H-NMR (CDCl₃) δ: 2.16 (tt, J=6.3, 6.3 Hz, 2H), 2.84 (s, 12H), 3.64 (dd,J=6.3, 6.3 Hz, 4H), 3.89 (s, 12H), 3.96 (s, 4H), 6.61 (d, J=9.0 Hz, 2H),6.66 (s, 4H), 7.66 (dd, J=2.2, 9.0 Hz, 2H), 8.41 (d, =2.2 Hz, 2H).

EXAMPLE 361,4-Bis[5-[3,5-dimethoxy-4-(1-pyrrolidinyl)phenyl]-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 17, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (280.0 mg, 0.680 mmol)synthesized in Reference Example 1 and1-bromo-3,5-dimethoxy-4-(1-pyrrolidinyl)benzene (436.0 mg, 1.52 mmol)synthesized from 4-bromo-2,6-dimethoxyaniline (Z. Naturforsch., B24(5),524-527(1969)). The crude crystals were recrystallized from methanol toyield the title compound as a pale brown crystalline powder (meltingpoint: 204.0-207.0° C.) (40.0 mg, yield: 9%).

¹H-NMR (CDCl₃) δ: 1.91-1.97 (m, 8H), 2.16 (tt, J=6.3, 6.3 Hz, 2H),3.26-3.33(m, 8H), 3.64 (dd, J=6.3, 6.3 Hz, 4H), 3.87 (s, 12H), 3.95 (s,4H), 6.61 (d, J=8.8 Hz, 2H), 6.69 (s, 4H), 7.66 (dd, J=2.2, 8.8 Hz, 2H),8.41 (d, J=2.2 Hz, 2H).

EXAMPLE 371,4-Bis[5-(4-methanesulfonylamino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

To a solution of1,4-bis[5-(4-amino-3,5-dimethoxyphenyl)-2-pyridyl)hexahydro-11,4-diazepinetetrahydrochloride (40.0 mg, 0.0570 mmol), which was synthesized inExample 34, in pyridine (1.0 mL) was added methanesulfonyl chloride(30.0 mg, 0.260 mmol). The reaction mixture was stirred for 15 minutes,and concentrated under reduced pressure. A solution of the residue inmethanol-chloroform (1:10) was washed with saturated aqueous sodiumhydrogencarbonate and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was recrystallized fromchloroform-hexane to yield the title compound as a pale browncrystalline powder (melting point: 235.0-239.0° C.) (28.0 mg, yield:68%).

¹H-NMR (CDCl₃) δ: 2.10-2.22 (m, 2H), 3.27 (s, 6H), 3.60-3.70 (m, 4H),3.93 (s, 12H), 3.97 (s, 4H), 6.13 (s, 2H), 6.63 (d, J=8.8 Hz, 2H), 6.70(s, 4H), 7.65 (dd, J=2.2, 8.8 Hz, 2H), 8.39 (d, J=2.2 Hz, 2H).

EXAMPLE 38 1,4-Bis[5-(4-fluoro3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, the title compound was obtained asa pale yellow amorphous powder (138.9 mg, yield: 93%) from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (110.0 mg, 0.270 mmol)synthesized in Reference Example 1 and4-fluoro-3,5-dimethoxyphenylboronic acid (160.0 mg, 0.800 mmol)synthesized from 1-bromo-4-fluoro-3,5-dimethoxybenzene (JP 10-87543A)synthesized by a similar procedure to that described in ReferenceExample 2.

¹H-NMR (CDCl₃) δ: 2.16 (tt, J=6.0, 6.03 Hz, 2H), 3.64 (dd, J=6.0, 6.0Hz, 4H), 3.93 (s, 12H), 3.95 (s, 4H), 6.62 (d, J=9.0 Hz, 2H), 6.71 (d,⁴J_(HF)=6.0 Hz, 4H), 7.63 (dd, J=3.0, 9.0 Hz, 2H), 8.36 (d, J=3.0 Hz,2H).

EXAMPLE 391,4-Bis[5-(4-chloro-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinedimethanesulfonate

Following the procedure of Example 1,1,4-bis[5-(4-chloro-73,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinewas obtained as a colorless crystalline powder (98.0 mg, yield: 82%)from 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (82.0 mg, 0.200mmol) synthesized in Reference Example 1 and4-chloro-3,5-dimethoxyphenylboronic acid (130.0 mg, 0.600 mmol)synthesized in Reference Example 10.

To a solution of1,4-bis[5-(4-chloro-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4diazepine (130.0 mg, 0.210 mmol) in methanol (5.0 mL) was added a 1.0 Maqueous methanesulfonic acid (0.45 mL, 0.45 mmol), and the reactionmixture was concentrated under reduced pressure. Ethanol (5.0 mL) wasadded to the residue, and the resulting mixture was concentrated underreduced pressure. The residue seas recrystallized frommethanol-chloroform-diethyl ether to yield the title compound as acolorless crystalline powder (melting point: 279.0-282.0° C.)(138.0 mg,yield: 83%).

¹H-NMR (DMSO-d₆, 120° C.) (ammonium salt NH⁺ protons were not observed)δ: 2.03 (tt, J=5.8, 5.8 Hz, 2H), 2.46 (s, 6H), 3.77(dd, J=5.8, 5.8 Hz,4H), 3.88 (s, 12H), 3.99 (s, 4H), 6.88 (s, 4H), 6.95 (d, J=9.0 Hz, 2H),7.94 (dd, J 2.6, 9.0 Hz, 2H), 8.35 (d, J=2.6 Hz, 2H).

EXAMPLE 401,4-Bis[5-(4-cyano-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, an oil was obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (124.0 mg, 0.300 mmol)synthesized in Reference Example 1 and4-cyano-3,5-dimethoxyphenylboronic acid (191.0 mg, 0.660 mmol)synthesized in Reference Example 11. Chloroform-hexane was added to theoil, and the resulting precipitate was collected by filtration to yieldthe title compound as a pale brown crystalline powder (melting point:≧300° C.) (16.0 mg, yield: 9%).

¹H-NMR (CDCl₃) δ: 2.16 (tt, J=6.1, 6.1 Hz, 2H), 3.66 (dd, J=6.1, 6.1 Hz,4H), 3.96 (s, 12H), 3.97 (s, 4H), 6.64 (d, J=8.9 Hz, 2 H), 6.65 (s, 4H),7.68 (dd, J=2.4, 8.9 Hz, 2H), 8.44 (d, J=2.4 Hz, 2H).

EXAMPLE 411,4-Bis[5-(3,5-dimethoxy-4-methylphenyl)-2-pyridyl]hexahydro-1,4-diazepinedimethanesulfonate

Following the procedure of Reference Example2,3,5-dimethoxy-4-methylphenylboronic acid was synthesized from1-iodo-3,5-dimethoxy-4-methylbenzene which had been synthesized as anintermediate in Reference Example 11.

Following the procedure of Example l,1,4-bis[5-(3,5-dimethoxy-4-methylphenyl)-2-pyridyl]hexahydro-1,4-diazepinewas obtained as a pale yellow oil (77.0 mg, yield: 58%) from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (100.0 mg, 0.240 mmol)synthesized in Reference Example 1 and3,5-dimethoxy-4-methylphenylboronic acid (]03.0 mg, 0.530 mmol).

To a solution of1,4-bis[5-(3,5-dimethoxy-4-methylphenyl)-2-pyridyl]hexahydro-1,4-diazepine(77.0 mg, 0.140 mmol) in methanol (5.0 mL) was added a 1.0 M aqueousmethanesulfonic acid (0.28 mL, 0.28 mmol), and the reaction mixture wasconcentrated under reduced pressure. Ethanol (5.0 mL) was added to theresidue, and the resulting mixture was concentrated under reducedpressure. The residue was recrystallized frommethanol-chloroform-diethyl ether to yield the title compound as a paleyellow crystalline powder (melting point: 235.0-237.0° C. (67.0 mg,yield: 64%).

¹H-NMR (CDCl₃) (data of the free base of the title compound) δ: 2.12 (s,6H), 2.17 (tt, J=6.0, 6.0 Hz, 2H), 3.64 (dd, J=6.0, 6.0 Hz, 4H), 3.87(s, 12H), 3.96 (s, 4H), 6.62 (d, J=9.0 Hz, 2H), 6.66 (s, 4H), 7.68 (dd,J=2.2, 9.0 Hz, 2H), 8.42 (d, J=2.2 Hz, 2H).

EXAMPLE 421,4-Bis[5-(4-hydroxymethyl-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 17, an oil (192.0 mg) containing1,4-bis[5-[4-(t-butyldimethylsiloxy)methyl-3,5-dimethoxyphenyl]-2-pyridyl]hexahydro-1,4-diazepine wasobtained from 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (128.0mg, 0.310 mmol) synthesized in Reference Example 1 and4-(t-butyldimethylsiloxy)methyl-3,5-dimethoxyphenyltrifluoromethanesulfonate (400.0 mg, 0.929 mmol) synthesized inReference Example 12.

To a solution of the oil (192.0 mg), which had been obtained by theabove procedure, in methanol (9.5 mL) was added 46% hydrofluoric acid(0.50 mL), and the resulting mixture was stirred at room temperature for30 minutes. A 5.0 M aqueous sodium hydroxide (5.0 mL) was added to thereaction mixture. The mixture was extracted with chloroform, and theorganic layer was concentrated under reduced pressure. The residue waspurified boy column chromatography on silica gel to give an oil. The oilwas recrystallized from methylene chloride-diethyl ether-hexane to yieldthe title compound as a slightly yellow crystalline powder (meltingpoint: >300.0° C.) (29.0 mg, yield: 16% based on1,4-bis(5-bromo-2-pyridyl)-hexahydro-1,4-diazepine).

¹H-NMR (CDCl₃) δ: 2.14-2.28 (m, 2H), 2.41 (br.t, J=5.9 Hz, 2H), 3.89 (s,12H), 3.55-4.15 (m, 8H), 4.80 (br.d, J=5.9 Hz, 4H), 6.64 (br.d, J=8.8Hz, 2H), 6.67 (s, 4H), 7.69 (br.d, J=8.8 Hz, 2H), 8.42 (br.s, 2H).

EXAMPLE 431,4-Bis[5-(4-ethoxycarbonyl-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 17, an oil was obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (243.0 mg, 0.590 mmol)synthesized in Reference Example 1 and4-ethoxycarbonyl-1-iodo-3,5-dimethoxybenzene (595.0 mg, 0.929 mmol)synthesized in Reference Example 13. The oil was recrystallized frommethylene chloride-diethyl ether-hexane to yield the title compound as apale brown crystalline powder (melting point: 244.0-245.0° C.)(75.1 mg,yield: 19%).

¹H-NMR (CDCl₃) δ: 1.38 (br.t, J=7.0 Hz, 6H), 2.12-2.25 (m, 2H), 3.87 (s,12H), 3.60-4.05 (m, 8H), 4.40 (br.q, J=7.0 Hz, 4H), 6.62 (br.d, J=8.8Hz, 2H), 6.66 (s, 4H), 7.66 (br.dd, J=2.4, 8.8 Hz, 2H), 8.40 (br.d,J=2.4 Hz, 2H).

EXAMPLE 441,4-Bis[5-(4-carboxy-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepineditrifluoroacetate

Following the procedure of Example 1,1,4-bis[5-(4-t-butoxycarbonyl-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinewas obtained-as a pale yellow oil (27.0 mg, yield: 25%) from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (62.0 mg, 0.150 mmol)synthesized in Reference Example 1 and4-t-butoxycarbonyl-3,5-dimethoxyphenylboronic acid (102.0 mg, 0.360mmol) synthesized in Reference Example 14.

To a solution of1,4-bis[5-(4-t-butoxycarbonyl-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4′-diazepine(27.0 mg, 0.037 mmol) in chloroform (4.0-mL) was added trifluroroaceticacid (0.3 mL), and the resulting mixture was stirred for 30 minutes. Thereaction mixture was concentrated under reduced pressure.Methanol-chloroform-diethyl ether-hexane was added to the residue andthe resulting precipitate was collected to yield the title compound as apale yellow crystalline powder [melting point: 164.5° C. (decomposed))(22.6 mg, yield: 72-1%).

¹H-NMR [CD₃OD-CDCl₃(1:10)] (neither ammonium salt NH⁺ protons norcarboxylic acid CO₂H protons were observed) δ: 2.12-2.28 (m, 2 H), 3.89(br.s, 12H), 3.70-4.07 (m, 8H), 6.69 (br.s, 4H), 6.82 (br.d, J=9.8 Hz,2H), 7.82 (br.d, J=9.8 Hz, 2H), 8.34 (br.s, 2H).

EXAMPLE 451,4-Bis[5-(4-acetyl-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinedimethanesulfonate

Following the procedure of Example 17,1,4-bis[5-(4-acetyl-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepinewas obtained as colorless crystalline powder (162.0 mg, yield: 53%) from1,4-bis(5-bromo-2-pyridyl)-hexahydro-1,4-diazepine (206.0 mg, 0.500mmol) synthesized in. Reference Example 1 and4-acetyl-3,5-dimethoxyphenyl trifluoro-methanesulfonate (410.0 mg, 1.250mmol) synthesized in Reference Example 15.

To a solution of1,4-bis[5-(4-acetyl-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine(80.0 mg, 0.130 mmol) in chloroform (5.0 mL), a 1.0 M solution ofmethanesulfonic acid in methanol (0.33 mL, 0.33 mmol) was added, and thereaction mixture was concentrated under reduced pressure. The residuewas recrystallized from methanol-diethyl ether to yield the titlecompound as a colorless crystalline powder (melting point: 236.0-238.0°C.) (94.8 mg, yield: 90%).

¹H-NMR (CDCl₃)(ammonium salt NH⁺ protons were not observed) δ: 2.34-2.42(m, 2H), 2.48 (s, 6H), 2.91 (s, 6H), 3.84 (s, 12H), 3.98-4.07 (m, 4H),4.3.1 (s, 4H), 6.61 (s, 4H), 7.41 (br.d, J=9.4 Hz, 2H), 8.15 (br.d,J=9.4 Hz, 2H), 8.43 (br.s, 2H).

EXAMPLE 461,4-Bis[5-(4-methoxy-3,5-dimethylphenyl)-2-pyridyl]hexahydro-1,4-diazepinedimethanesulfonate

Following the procedure of Example 1,1,4-bis[5-(4-methoxy-3,5-dimethylphenyl)-2-pyridyl]hexahydro-1,4-diazepinewas obtained as a colorless crystalline powder (130.0 mg, yield: 82%)from 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (123.0 mg, 0.300mmol) synthesized in Reference Example 1 and4-methoxy-3,5-dimethylphenylboronic acid (152.0 mg, 0.900 mmol)synthesized from 1-bromo-4-methoxy-3,5-dimethylbenzene (TetrahedronLett., 30, 735-738(1989)) by a similar procedure as in Reference Example2.

To a solution of1,4-bis[5-(4-methoxy-3,5-dimethylphenyl)-2-pyridyl]hexahydro-1,4-diazepine(126.0 mg, 0.240 mmol) in methanol (10 mL) was added a 1.0 M aqueousmethanesulfonic acid (0.50 mL, 0.50 mmol), and the reaction mixture wasconcentrated under reduced pressure. Ethanol (10 mL) vas added to theresidue, and the resulting mixture was concentrated under reducedpressure. The residue was recrystallized from ethanol-diethylether-hexane to yield the title compound as a colorless crystallinepowder (melting point: 250.0-253.0° C.)(157.0 mg, yield: 91%).

¹H-NMR (DMSO-d₆, 120° C.) (ammonium salt NH⁺ protons were not observed)δ: 2.01 (tt, J=5.8, 5.8 Hz, 2H), 2.24 (s, 12H), 2;45 (s, 6H), 3.68 (s,6H), 3.77 (dd, J=5.8, 5.8 Hz, 4H), 4.00 (s, 4H), 6.98 (d, J=9.0 Hz, 2H),7.14 (s, 4H), 7.86 (dd, J=2.4, 9.0 Hz, 2H), 8.15 (d, J=2.4 Hz, 2H).

EXAMPLE 471,4-Bis[5-(3-formyl-2-furyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, the title compound was obtained asa brown amorphous powder (8.0 mg, yield: 9%) from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (82.0 mg, 0.200 mmol)synthesized in Reference Example 1 and 3-formylfuran-2-boronic acid(62.0 mg, 0.440-mmol).

¹H-NMR (CDCl₃) o: 2.15 (tt, J=6.0, 6.0 Hz, 2H), 3.68 (dd, J=6.0, 6.0 Hz,4H), 3.99 (s, 4H), 6.65 (d, J=9.0 Hz, 2H), 6.87 (d, J=2.1 Hz, 2H), 7.42(d, J=2.1 Hz, 2H), 7.87 (dd, J=2.4, 9.0 Hz, 2H), 8.57 (d, J=2.4 Hz, 2H),10.04 (s, 2H).

EXAMPLE 48 1,4-Bis[5-(3-thienyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (82.0 mg, 0.200 mmol)synthesized in Reference Example 1 and thiophene-3-boronic acid (56.0mg, 0.44 mmol). Methanol-chloroform-diethyl ether was added to the crudecrystals and the resulting precipitate novas collected by filtration toyield the title compound as brown needles (melting-point: 234.0-236.0°C.) (35.0 mg, yield: 42%).

¹H-NMR (CDCl₃) δ: 2.14 (tt, J=6.3, 6.3 Hz, 2H), 3.61 (dd, J=6.3, 6.3 Hz,4H), 3.93 (s, 4H), 6.58 (d, J=9.0 Hz, 2H), 7.28-7.33 (m, 4H), 7.36-7.39(m, 2H), 7.66 (dd, J=2.4, 9.0 Hz, 2H), 8.44 (d J=2.4 Hz, 2H).

EXAMPLE 491,4-Bis[5-(2-formyl-3-thienyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, the title compound was obtained asa pale yellow amorphous powder (71.0 mg, yield: 74%) from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (82.0 mg, 0.200 mmol)synthesized in Reference Example 1 and 2-formylthiophene-3-boronic acid(69.0 mg, 0.44 mmol).

¹H-NMR (DMSO-d₆, 120° C.) δ: 2.02 (tt, J=6.0, 6.0 Hz, 2H), 3.71 (dd,J=6.0, 6.0 Hz, 4H), 3.94 (s, 4H), 6.77 (d, J=8.7 Hz, 2H), 7.27 (d, J=4.8Hz, 2H), 7.65 (dd, J=2.6, 8.7 Hz, 2H), 7.97 (dd, J=1.2, 4.8 Hz, 0.2H),8.25 (d, J=2.6 Hz, 2H), 9.78 (d, J=]0.2 Hz, 2H).

EXAMPLE 50 1,4-Bis[5-(2-thienyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (82.0 mg, 0.200 mmol)synthesized in Reference Example 1 and thiophene-2-boronic acid (56.0mg, 0.44 mmol). Methanol-chloroform-diethyl ether was added to the crudecrystals and the resulting precipitate was collected by filtration toyield the title compound as a brown crystalline powder (melting point:170.0-172.0° C.)(21.0 mg, yield: 25%).

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.99 (tt, J=6.0, 6.0 Hz, 2H), 3.65 (dd,J=6.0, 6.0 Hz, 4H), 3.88 (s, 4H), 6.91 (d, J=9.0 Hz, 2H), 7.03 (dd,J=3.4, 5.1 Hz, 2H), 7.19 (dd, J=1.2, 3.4 Hz, 2H), 7.30 (dd, J=1.2, 5.1Hz, 2H), 7.65 (dd, J=2.6, 9.0 Hz, 2H), 8.31 (d, J=2.6 Hz, 2 H).

EXAMPLE 511,4-Bis[5-(5-acetyl-2-thienyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, the title compound was obtained asa yellow amorphous powder (12.0 mg, yield: 11%) from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (82.0 mg, 0.200 mmol)synthesized in Reference Example 1 and 5-acetylthiophene-2-boronic acid(75.0 mg, 0.44 mmol).

¹H-NMR (DMSO-d₆, 120° C.) δ: 1.99 (tt, J=6.0, 6.0 Hz, 2H), 2.46 (s, 6H),3.67 (dd, J=6.0, 6.0 Hz, 4H), 3.91 (s, 4H), 6.72 (d, J=9.0 Hz, 2H), 7.29(d) J=4.1 Hz, 2H), 7.72 (dd, J=2.4, 9.0 Hz, 2H), 7.73 (d, J=4.1 Hz, 2H),8.42 (d, J=2.4 Hz, 2H).

EXAMPLE 52 1,4-Bis[5-(3-pyridyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (82.0 mg, 0.200 mmol)synthesized in Reference Example 1 and pyridine-3-boronic acid (54.0 mg,0.44 mmol). The crude crystals were recrystallized fromchloroform-hexane to yield the title compound as colorless flakes(melting point: 210.0-211.0° C.) (38.0 mg, yield: 45%).

¹H-NMR (CDCl₃) δ: 2.17 (tt, J=6.0, 6.0 Hz, 2H), 3.65 (dd, J=6.0, 6.0 Hz,4H), 3.97 (s, 4H), 6.66 (d, J=9.0 Hz, 2H), 7.33 (dd, J=4.8, 7.8 Hz, 2H),7.68 (dd, J=2.4, 9.0 Hz, 2H), 7.80 (ddd, J=1.7, 2.1, 7.8 Hz, 2H), 8.41(d, J=2.4 Hz, 2H), 8.53 (dd, J=1.7, 4.8 Hz, 2H), 8.78 (d, J=2.1 Hz, 2H).

EXAMPLE 53 1,4-Bis[5-(2-benzo[b]furyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (82.0 mg, 0.200 mmol)synthesized in Reference Example 1 and benzo[b]furan-2-boronic acid(71.0 mg, 0.44 mmol). Methanol-chloroform-diethyl ether was added to thecrude crystals and the resulting precipitate was collected by filtrationto yield the title compound as a colorless crystalline powder [meltingpoint: 245.0° C. (decomposed)] (17.0 mg, yield: 17%).

¹H-NMR (DMSO-d₆, 120° C.) δ: 2.02 (tt, J=6.0, 6.0 Hz, 2H), 3.70 (dd,J=6.0, 6.0 Hz, 4H), 3.94 (s, 4H), 6.77(d, J=9.0 Hz, 0.2H), 6.97-6.99 (m,2H), 7.14-7.23 (m, 4H), 7.44-7.56 (m, 4H), 7.87 (dd, J=2.4, 9.0 Hz, 2H),8.57 (d, J=2.4 Hz, 2H).

EXAMPLE 541,4-Bis[5-(2-benzo[b]thienyl)-2-pyridyl]hexahydro-1,4-diazepine

Following the procedure of Example 1, crude crystals were obtained from1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (82.0 mg, 0.200 mmol)synthesized in Reference Example 1 and benzo[b]thiophene-2-boronic acid(78.0 mg, 0.44 mmol). Methanol-chloroform-diethyl ether was added to thecrude crystals and the resulting precipitate was collected by filtrationto yield the title compound as a colorless crystalline powder [meltingpoint: 246.0° C. (decomposed)] (41.0 mg, yield: 39%).

¹H-NMR (DMSO-d₆, 120° C.) δ: 2.01 (tt, J=6.0, 6.0 Hz, 2H), 3.69 (dd,J=6.0, 6.0 Hz, 4H), 3.92 (s, 4H), 6.75 (d, J=9.0 Hz, 2H), 7.20-7.35 (m,4H), 7.49 (s, 2H), 7.67-7.75 (m, 2H), 7.77 (dd, J=2.4, 9.0 Hz, 2H),7.80-7.84 (m, 2H), 8.43 (d, J=2.4 Hz, 2H).

EXAMPLE 55 1,4-Bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]piperazinedimethanesulfonate

Following the procedure of Example 1,1,4-bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]piperazine was obtained asa colorless crystalline powder (147.0 mg, yield: 52%) from1,4-bis(5-bromo-2-pyridyl)piperazine (199.0 mg, 0.500 mmol) synthesizedin a similar manner to that described in Reference Example 1 and3,4,5-trimethoxyphenylboronic acid (318.0 mg, 1.50 mmol).

To a solution of 1,4-bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]piperazine(147.0 mg, 0.257 mmol) in methylene chloride (5.0 mL) was added a 1.0 Msolution of methanesulfonic acid in methanol (0.54 mL, 0.54 mmol), andthe reaction mixture was concentrated under reduced pressure. Theresidue was recrystallized from methylene chloride-diethyl ether toyield the title compound as a pale yellow crystalline powder (meltingpoint: 238.0-239.0° C.) (160.8 mg, yield: 82%).

¹H-NMR (CD₃OD) (ammonium salt NH⁺ protons were not observed) δ: 2.72 (s,6H), 3.82 (s, 6H), 3.93 (s, 12H), 4.09 (s, 8H), 6.89 (s, 4H), 7.44 (d,J=9.5 Hz, 2H), 8.24 (s, 2H), 8.38 (d, J=9.5 Hz, 2H).

EXAMPLE 564,8-Bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]-1,4,8-triazabicyclo[4.4.0]decane

Following the procedure of Example 1, the title compound was obtained asa pale brown amorphous powder (89.9 mg, yield: 71%) from4,8-bis(5-bromo-2-pyridyl)-1,4,8-triazabicyclo-[4.4.0]decane (91.7 mg,0.202 mmol) synthesized in a similar manner to that described inReference Example 1 and 3,4,5-trimethoxyphenylboronic acid (133.3 mg,0.629 mmol).

¹H-NMR (CDCl₃) δ: 2.37 (br.tt, J=2.3, 12.0 Hz, 1H), 2.43 (ddd, J=3.2,12.0, 12.0 Hz, 2H), 2.78 (dd, J=12.0, 12.0 Hz, 2H), 2.99 (br.d, J=12.0Hz, 2H), 3.15 (ddd, J=2.7, 12.0, 12.0 Hz, 2H), 3.88 (s, 6 H), 3.92 (s,12H), 4.25 (br.d, J=12.0 Hz, 2H), 4.33 (br.d, J=12.0 Hz, 2H), 6.70 (s,4H), 6.74 (d, J=8.8 Hz, 2H), 7.70 (dd, J=2.5, 8.8 Hz, 2H), 8.42 (d,J=2.5 Hz, 2H).

EXAMPLE 571,3-Bis[4-[5-(3,4,5-trimethoxyphenyl)-%2-pyridyl)-1-piperazinyl]propane

Following the procedure of Example 1, an oil was obtained from1,3-bis[4-(5-bromo-2-pyridyl)-1-piperazinyl]propane (196.0 mg, 0.370mmol) synthesized in a similar manner to that described in ReferenceExample 1 and 3,4-5-trimethoxyphenylboronic acid (244.0 mg, 1.32 mmol).The oil was recrystallized from chloroform-hexane to yield the titlecompound was obtained as a colorless crystalline powder (melting point:175.0-176.0° C.) (78.4 mg, yield: 34%).

¹H-NMR (CDCl₃) δ: 1.82 (br.quint, J=7.4 Hz, 2H), 2.48 (br.t, J=7.4 Hz,4H), 2.61 (br.dd, J=4.7, 4.7 Hz, 8H), 3.62 (br.dd, J=4.7, 4.7 Hz, 8H),3.88 (s, 6H), 3.91 (s, 12H), 6.70 (s, 4H), 6.72 (d, J=8.9 Hz, 2H), 7.68(dd, J=2.5, 8.9 Hz, 2H), 8.41 (d, J=2.5 Hz, 2H).

EXAMPLE 58N,N′-Bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]-N,N′-dimethylethylenediaminedimethanesulfonate

Following the procedure of Example 1,N,N′-bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]-N,N′-dimethylethylenediaminewas obtained as a pale yellow oil (40.0 mg, yield: 56%) fromN,N′-bis(5-bromo-2-pyridyl)-N14N′-dimethylethylenediamine (50.0 mg,0.120 mmol) synthesized in a similar manner to that described inReference Example 1 and 3,4,5-trimethoxyphenylboronic acid (79.5 mg,0.375-mmol).

To a solution ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]-N,N′-dimethylethylenediamine(40.0-mg, 0.070 mmol) in methanol (5.0 mL) was added a 1.0 M aqueousmethanesulfonic acid (0.14 mL, 0.14 mmol), and the reaction mixture wasconcentrated under reduced pressure. Ethanol (5.0 mL) was added to theresidue, and the mixture was concentrated under reduced pressure. Theresidue was recrystallized from methanol-diethyl ether to yield thetitle compound as a pale, yellow crystalline powder (melting point:204.0-206.0° C.) (32.0 mg, yield: 60%).

¹H-NMR (DMSO-d₆, 120° C.) (ammonium salt NH⁺ protons were not observed)δ: 2.41 (s, 6H), 3.15 (s, 6H), 3.73 (s, 6H), 3.84 (s, 12H), 3.88 (s,4H), 6.83 (s, 4H), 6.91 (d; J=9.0 Hz, 2H), 7.93 (dd, J=2.4, 9.0 Hz, 2H),8.30 (d, J=2.4 Hz, 2H).

Test 1 (Evaluation of IgE Antibody Production Inhibiting Activity).

From a mouse (Balb/C, male, 8 weeks old), the spleen was enucleated. Thespleen was shredded in 10% FEB/RPMI 1640, and was then disintegratedinto single cells through a 70-mesh screen. Those single cells werehemolyzed with Gey's solution, and using RPMI 1640 medium/25 mMHEPES/0.3% BSA, a spleen cell suspension (1×10⁷ cells/mL) was prepared.After an aliquot of the suspension was reacted with a rat anti-mouseThy-1.2 monoclonal antibody (product of Cedarlane Laboratories Limited)at 4° C. for 1 hour, centrifugation was conducted. Precipitated cellswere suspended again (1×10⁷ cells/mL, RPMI/HEPES/BSA). After thesuspension was next reacted with a low-cytotoxic rabbit complement(product of Cedarlane Laboratories Limited) at 37° C. for 1 hour, deadcells were removed by specific gravity centrifugation using Lympholyte M(product of Cedarlane Laboratories Limited) so that a B cell fractionwas obtained as viable cells.

Using a 96-well plate, the B cells (2×10⁵ cells/0.2 mL/well) wereincubated together with LPS (E. coli 026:B6, product of DIFCOLaboratories, Inc.) for 1 day. Mouse IL4: (product of Genzyme Corp.) wasthen added, followed by further incubation for. 6 days.

The IgE antibody production inhibiting activity of each drug wascalculated by adding the drug Day 1 of the incubation and assaying thequantity of IgE in the culture supernatant by ELISA after the incubationinhibition activity (IC₅₀) is presented in Table 1.

Further, the solubility (%) of each compound in water was alsoestimated. The results are presented in Table 1. TABLE 1 Compound(Example No.) IC₅₀ (μM) Water solubility (%) 26 0.2 5 34 0.3 5 35 0.2 5* 57 0.1  5* 58 0.2 5*Solubility in 0.1 M hydrochloric acid

Industrial Applicability

The bis(5-aryl-2-pyridyl) derivatives (1) according to the presentinvention and salts thereof have excellent IgE antibody productioninhibiting activity and are useful as medicinal agents for theprevention or treatment of allergic immune diseases.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

1. A compound represented by formula (1) or a salt thereof:

wherein A is a substituted or unsubstituted aromatic hydrocarbon groupor a substituted or unsubstituted aromatic heterocyclic group, and X isa group selected from the group consisting of moieties having formula(4) to (5):

wherein, in formula (4), R is hydrogen or a lower alkyl group and p isan integer of 1 to
 6. 2. The bis(aryl-2-pyridyl) compound or saltthereof according to claim 1, wherein, A is a substituted orunsubstituted phenyl group, a substituted or unsubstituted pyridylgroup, a substituted or unsubstituted thienyl, a substituted orunsubstituted furyl group, a substituted or unsubstituted benzofurylgroup or a substituted or unsubstituted benzothienyl group.
 3. Thebis(aryl-2-pyridyl) compound or salt thereof according to claim 2,wherein, A is a substituted or unsubstituted phenyl group.
 4. Thebis(aryl-2-pyridyl) compound or salt thereof according to claim 2,wherein said aromatic hydrocarbon group or said aromatic heterocyclicgroup is substituted by 1 to 3 substituents selected from the groupconsisting of lower alkyl groups, halogeno(lower alkyl) groups,hydroxy(lower alkyl) groups, lower alkoxy(lower alkyl) groups, loweralkoxy groups, halogen, hydroxy, cyano, (lower alkyl)thio groups, amino,mono- or di-(lower alkyl)amino groups, (lower alkyl)sulfonylaminogroups, formyl, carboxyl, (lower alkoxy)carbonyl groups, lower alkanoylgroups, pyrrolidinyl, and alkylenedioxy groups.
 5. (canceled)
 6. Thebis(aryl-2-pyridyl) compound or a salt thereof according to claim 1,wherein the lower alkyl moiety in the lower alkyl group containinggroups is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, pentyl, hexyl, cyclopropyl or cyclohexyl.
 7. Thebis(aryl-2-pyridyl) compound or a salt thereof according to claim 1,wherein said 1 to 3 substituents are selected from the group consistingof methyl, t-butyl, methoxy, ethoxy, isopropoxy, fluorine, chlorine,hydroxy, cyano, methylthio, dimethylamino, pyrrolidinyl, formyl,carboxyl, ethoxycarbonyl, t-butoxycarbonyl, propionyloxy, acetyl,methylenedioxy, methoxycarbonyl, hydroxymethyl, methoxymethyl, amino,methanesulfonylamino, and trifluoromethyl.
 8. The compound or a saltthereof according to claim 4, wherein said bis(5-aryl-2-pyridyl)compound isN,N′-bis[5-(3,4,5-trimethoxyphenyl)-2-pyridyl]-N,N′-dimethylethylenediaminedimethanesulfonate.
 9. A medicinal composition, comprising, as an activeingredient, an effective amount of the bis(aryl-2-pyridyl) compound or asalt thereof according to claim 1 and a pharmacologically acceptablecarrier.
 10. The medicinal composition according to claim 9, which iseffective in the prevention or therapeutic treatment of an allergicimmune disease.
 11. The medicinal composition according to claim 10,which said allergic immune disease is asthma, atopic dermatitis,allergic rhinitis, inflammatory bowel disease, contact dermatitis or anallergic ophthalmopathy.
 12. An IgE antibody production inhibitor whichis a bis(aryl-2-pyridyl) compound or a salt thereof represented byformula (1) or a salt thereof,

wherein A is a substituted or unsubstituted aromatic hydrocarbon groupor a substituted or unsubstituted aromatic heterocyclic group and X is agroup selected from the group consisting of moieties having formula (2)to (5):

wherein, in formula (2), m is an integer of 1 or 2, and in formula (3),n is an integer of 1 to 6; and in formula (4), R is hydrogen or a loweralkyl group and p is an integer of 1 to
 6. 13. (canceled)
 14. A methodof treating a subject suffering from an allergic immune disease, whichcomprises: administering an effective amount of the bis(aryl-2-pyridyl)compound or a salt thereof represented by formula (1) or a salt thereof:

wherein A is a substituted or unsubstituted aromatic hydrocarbon groupor a substituted or unsubstituted aromatic heterocyclic group, and X isa group selected from the group consisting of moieties having formula(2) to (5);

wherein, in formula (2), m is an integer of 1 or 2, and in formula (3) nis an integer of 1 to 6; and in formula (4), R is hydrogen or a lowera]kyl group and p is an integer of 1 to 6, to said subject.